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Shi G, Tian H, Chu S, Liu D, Yan Z, Yang M, Xu H. Design, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics. Bioorg Med Chem Lett 2025; 124:130255. [PMID: 40286989 DOI: 10.1016/j.bmcl.2025.130255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound 1) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. 1 demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that 1 effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and in vivo imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.
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Affiliation(s)
- Ge Shi
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Hua Tian
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shiji Chu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Dan Liu
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zheng Yan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Min Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beiiing 100050, China.
| | - Heng Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
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Hou B, Jia G, Li Z, Jiang Y, Chen Y, Li X. Discovery of hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells. Eur J Med Chem 2025; 292:117658. [PMID: 40300459 DOI: 10.1016/j.ejmech.2025.117658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/08/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025]
Abstract
PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor 11h. Representative compound 31f possessed both PI3K (IC50 = 2.5-80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC50 = 1.9-75.5 nM for HDAC1-3). 31f showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule 39a, a HDAC inhibitor structurally similar to 31f. In the mantle cell lymphoma Jeko-1 cell line, 31f showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.
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Affiliation(s)
- Baogeng Hou
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Geng Jia
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Zhongqiang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuqi Jiang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuxin Chen
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Xiaoyang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.
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Lv JM, Wang LX, Yang J, Dong JJ, Feng NN, Liu HG, Zhao N, Yin GL, Wang F. UPLC-Q-TOF-MS based investigation into the bioactive compounds and molecular mechanisms of Qishen Huanwu capsule attenuates anthracycline-induced cardiotoxicity. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156877. [PMID: 40449451 DOI: 10.1016/j.phymed.2025.156877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 05/14/2025] [Accepted: 05/18/2025] [Indexed: 06/03/2025]
Abstract
BACKGROUND Cardiotoxicity is a prevalent side effect linked to anthracyclines, a class of chemotherapy drugs, that frequently leads to the discontinuation of anthracycline-based treatments among cancer patients. Thus, there is a pressing need to mitigate and prevent these cardiotoxic effects. Mounting evidence suggests that Traditional Chinese Medicine may alleviate the toxic side effects of chemotherapy agents. For this reason, this study seeked to comprehensively assess the cardioprotective properties of the Qishen Huanwu capsule (QSHWC) against pirarubicin (THP)-induced cardiotoxicity in rat models and explore the underlying mechanisms. METHODS The effects of QSHWC on anthracycline-induced myocyte damage was evaluated via CCK8 assay. Investigations conducted subsequently principally comprised network pharmacology methodology, Ultra-performance liquid chromatograph-hybrid quadrupole orbitrap high resolution mass spectrometer (UHPLC-Q-Orbitrap HRMS) and an anthracycline-induced cardiotoxicity (AIC) rat model to dig into the chemical constituents and potential therapeutic mechanisms of the QSHWC. RESULTS As evidently demonstrated by in-vitro studies, QSHWC not only effectively elevated the cell viability of H9c2 after anthracycline injury, but also downregulates NLRP3 expression and LDH release. As illustrated by in-vivo studies, medium and high doses of QSHWC improved the cardiac injury caused by pirarubicin, decreased myocardial injury scores, cTnT and NT-proBNP levels, and elevated the left ventricular ejection fraction (LVEF %). By conducting HPLC-Q-Exactive-MS analysis, we identified the major parts of the QSHWC. As suggested by network pharmacology and molecular docking analyses, QSHWC may exert cardioprotective protective effects by regulating multiple signaling pathways such as PI3K/AKT and NOD-like receptors. Last but not least, animal experiments confirmed that QSHWC can up-regulate phosphorylated PI3K and phosphorylated AKT in rat myocardial tissue, while down-regulating NLRP3 levels. CONCLUSION QSHWC alleviates anthracycline-induced cardiotoxicity by targeting cardiac pyroptosis through the PI3K/AKT pathway, while providing a multi-target therapeutic strategy.
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Affiliation(s)
- Jin-Meng Lv
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China; Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine in Osteoarthrosis Research, China
| | - Li-Xin Wang
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Jing Yang
- Department of Cardiovascular Disease, Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Jing-Jing Dong
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Na-Na Feng
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Hong-Gui Liu
- Department of Cardiovascular Disease, Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Na Zhao
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Guang-Li Yin
- Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China
| | - Feng Wang
- Department of Cardiovascular Disease, Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, China.
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Liu X, Liu L, Ren X, Chen Y, Yin M, Xie H, Sun T, Tan Y, Wang S, Xu D, Tang S. Unveiling XinJia-LuHuang Granules' protective mechanism against atherosclerosis: Integrating network pharmacology, metabolomics, and experimental validation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156919. [PMID: 40466509 DOI: 10.1016/j.phymed.2025.156919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 05/21/2025] [Accepted: 05/26/2025] [Indexed: 06/16/2025]
Abstract
BACKGROUND Atherosclerosis (AS) is a primary contributor to cardiovascular disease. XinJia-LuHuang Granules (XLG), a formula used in traditional Chinese medicine (TCM), has been employed to treat AS. However, the underlying mechanism through which XLG exerts its effects remains unclear and warrants further investigation. PURPOSE The purposes of this research are to assess the therapeutic effect of XLG on AS and to investigate its potential underlying procedures. MATERIALS AND METHODS Network pharmacology was implemented to recognize XLG's active ingredients, along with their associated targets and pathways involved in the treatment of AS. Metabolomics was employed to detect changes in metabolites following XLG administration. Furthermore, a combined analysis of metabolomics and network pharmacology elucidated the key targets and pathways underlying the therapeutic effects of XLG in AS. The interactions between XLG's active ingredients and their specific targets were evaluated using molecular docking. In addition, an apolipoprotein E knockout (ApoE-/-) mouse model was used to simulate AS. Hematoxylin-Eosin (HE) staining and Oil Red O staining were utilized to assess the extent of pathological changes. An enzyme-linked immunosorbent assay (ELISA) was employed to measure inflammatory responses. The biochemical analyzer was applied to evaluate serum lipid levels in the mice. Immunofluorescence (IF) staining was conducted to measure the expression levels of key proteins in the sphingosine-1-phosphate receptor 1 (S1PR1)-activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signaling pathway. In cell experiments, the viability of human umbilical vein endothelial cells (HUVECs) was detected using Cell Counting Kit-8 (CCK-8). Western blot (WB) analysis and ELISA were executed to measure the expression levels of proteins in the S1PR1-activated PI3K/Akt/eNOS signaling pathway both before and after the administration of specific inhibitors. RESULTS XLG contains 143 active ingredients and 309 potential targets, of which 193 are associated with AS. Metabolomic analysis revealed alterations in lipid substance levels. Combined with molecular docking analysis, it was observed that the principal active ingredients of XLG interact directly with these targets, potentially exerting anti-AS effects through the PI3K/Akt/eNOS signaling pathway. Animal experiments found that XLG reduced blood lipid levels and inflammatory cytokine content in AS mice. Additionally, the expression levels of PI3K, AKT, eNOS, and S1PR1 were significantly upregulated following XLG administration. Furthermore, XLG promoted the proliferation of HUVECs in response to lipopolysaccharide stimulation and improved vascular function through the S1PR1-activated PI3K/Akt/eNOS signaling pathway. Conversely, the therapeutic efficacy of XLG was diminished upon administration of an S1PR1 inhibitor. CONCLUSION Our research indicates that XLG may employ the S1PR1-activated PI3K/Akt/eNOS signaling pathway to produce its anti-AS actions. This research improves our understanding of the underlying mechanism by which XLG treats AS, providing a promising therapeutic approach for managing the condition.
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Affiliation(s)
- Xueqian Liu
- Nanjing University of Chinese Medicine, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China, 140 Renmin South Road, Taicang 215400, China; Nanjing University of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing 210029, China.
| | - Lele Liu
- School of Integrated Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia District, Nanjing 210023, China.
| | - Xiang Ren
- Nanjing University of Chinese Medicine, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China, 140 Renmin South Road, Taicang 215400, China.
| | - Yunhu Chen
- Nanjing University of Chinese Medicine, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China, 140 Renmin South Road, Taicang 215400, China.
| | - Moqing Yin
- Nanjing University of Chinese Medicine, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China, 140 Renmin South Road, Taicang 215400, China.
| | - Haitao Xie
- Nanjing University of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing 210029, China.
| | - Tong Sun
- Nanjing University of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing 210029, China.
| | - Yali Tan
- School of Integrated Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia District, Nanjing 210023, China.
| | - Shi Wang
- Nanjing University of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing 210029, China.
| | - Dan Xu
- Nanjing University of Chinese Medicine, Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China, 140 Renmin South Road, Taicang 215400, China.
| | - Shuhua Tang
- Nanjing University of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing 210029, China.
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Fang X, Li J, Pang H, Zheng H, Shi X, Feng L, Hu K, Zhou T. Xingxiao pills suppresses lung adenocarcinoma progression by modulating lipid metabolism and inhibiting the PLA2G4A-GLI1-SOX2 Axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156826. [PMID: 40339555 DOI: 10.1016/j.phymed.2025.156826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/20/2025] [Accepted: 05/02/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear. PURPOSE To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation. METHOD UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant). RESULTS XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group. CONCLUSION Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.
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Affiliation(s)
- Xueni Fang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - JingHua Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - HaoYue Pang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hao Zheng
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiang Shi
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kaiwen Hu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Tian Zhou
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
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Gao M, Cheng Z, Yan W, Zhang Z, Zhang L, Geng H, Xu Y, Li C. Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca 2+ overload through the inhibition of phosphoinositide 3-kinase activity. Biochem Biophys Res Commun 2025; 771:152027. [PMID: 40403685 DOI: 10.1016/j.bbrc.2025.152027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/24/2025] [Accepted: 05/14/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND Tyrosine kinase inhibitors (TKIs) are commonly used in cancer treatment, but their off-target effects can lead to serious cardiotoxicity. Our previous studies have revealed that upregulation of phosphoinositide 3-kinase (PI3K) confers considerable protection against calcium (Ca2+) disorders and cardiac dysfunction induced by sunitinib. However, the involvement of PI3K inhibition in the prevention of cardiomyocyte contraction induced by other TKIs remains unclear. METHODS Herein, we selected three TKIs with different targets and mechanisms, namely, sunitinib, imatinib, and trametinib, and assessed their myocardial toxicity, PI3K activity, and Ca2+ regulation in AC16 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). RESULTS All three TKIs induced AC16 cell damage and reduced PI3K expression. These drugs also caused hiPSC-CM injury, increased reactive oxygen species (ROS) release, induced cytoplasmic Ca2+ overload, and inhibited cell contraction. Phosphatidylinositol (3,4,5)-trisphosphate pretreatment and adenovirus-mediated p110α overexpression activated PI3K, prevented TKI-induced Ca2+ overload and ROS release, and reduced TKI-induced myocardial injury and contraction inhibition. CONCLUSIONS All three TKIs induced cardiotoxicity by inhibiting PI3K activity.
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Affiliation(s)
- Meiling Gao
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China; Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China
| | - Zhiling Cheng
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China; Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China
| | - Wei Yan
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China
| | - Zhihan Zhang
- Department of Nutrition, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ling Zhang
- Department of Pharmacy, Hebei Chest Hospital, Shijiazhuang, Hebei, China
| | - Hui Geng
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China
| | - Yanfang Xu
- Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China.
| | - Congxin Li
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China.
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Jiang M, Ma S, Xuan Y, Chen K. Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy. Eur J Med Chem 2025; 291:117626. [PMID: 40252381 DOI: 10.1016/j.ejmech.2025.117626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/21/2025]
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRASG12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRASG12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.
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Affiliation(s)
- Min Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Shaowei Ma
- Department of Interventional Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Xuan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Kuanbing Chen
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
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Zhong Y, Jiao P, Wang Y, Mao B, Huang H, Shi C, Sun X, Liu Z, Zhang L. Discovery of novel PI3KC2γ inhibitors with high potency, selectivity, and favorable pharmacokinetics for glycogen metabolism regulation. Eur J Med Chem 2025; 291:117621. [PMID: 40262302 DOI: 10.1016/j.ejmech.2025.117621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/11/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025]
Abstract
Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P2 production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P2 formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.
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Affiliation(s)
- Yi Zhong
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Peili Jiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuxi Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Beibei Mao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Han Huang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Cheng Shi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiaojiao Sun
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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Li L, Liu Q, Shao Y, Wang S, Liu S, Wang X, Wang S, Ren D. Gaudichaudion H inhibits KRAS-mutant pancreatic cancer cell growth through interfering PDEδ-KRAS interaction. Chem Biol Interact 2025; 415:111529. [PMID: 40288433 DOI: 10.1016/j.cbi.2025.111529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 04/03/2025] [Accepted: 04/25/2025] [Indexed: 04/29/2025]
Abstract
KRAS mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome KRAS-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from Garcinia oligantha. In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from G. oligantha. Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with KRAS mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.
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Affiliation(s)
- Lingyu Li
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Qingying Liu
- School of Pharmaceutical Sciences, Shandong Xiandai University, PR China
| | - Yuyu Shao
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuo Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuangyu Liu
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Xiaoning Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuqi Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China.
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10
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Wang X, Wang Z, Liu Z, Huang F, Pan Z, Zhang Z, Liu T. Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response. Biochim Biophys Acta Rev Cancer 2025; 1880:189322. [PMID: 40228747 DOI: 10.1016/j.bbcan.2025.189322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Abstract
Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.
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Affiliation(s)
- Xueying Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zeyao Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zihan Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Fanxuan Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zhaoyu Pan
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
| | - Zhiren Zhang
- Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China; Departments of Cardiology and Pharmacy and Breast Cancer surgery, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases, Harbin, China.
| | - Tong Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China; Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
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11
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Goloudina A, Le Chevalier F, Authié P, Charneau P, Majlessi L. Shared neoantigens for cancer immunotherapy. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200978. [PMID: 40256120 PMCID: PMC12008704 DOI: 10.1016/j.omton.2025.200978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Exploration of neoantigens holds the potential to be productive in immuno-oncotherapy. Among tumor-specific antigens, neoantigens result from genetic instability that gives rise to non-synonymous somatic mutations, highly specific to tumor cells. In addition to point mutations, gene rearrangements, indels leading to frameshifts, chromosomal translocations or inversions that may lead to fusion proteins, alternative mRNA splicing, and integration of genetic material of oncogenic viruses into the host genome provide consistent sources of neoantigens that are absent in healthy tissues. Out of these alterations, 2%-3% may generate T cell neoepitopes, possibly detectable by TCRs. Neoantigens are absent in healthy tissues and are thus at low risk of triggering autoimmunity. In addition, the host lymphocytes have not been rendered tolerant toward them and it is possible to induce immune responses against them. Here, we overview the two categories of neoantigens, i.e., private and shared, and their use in immuno-oncotherapy in selected pre-clinical and clinical studies. The vast majority of commonly occurring tumor-specific mutations are cancer causing and are permanently expressed by all malignant tumor cells, preventing the latter from escaping vaccine-induced anti-neoantigen immunity. The use of public neoantigens combined with efficient vaccine platforms can provide non-personalized "off-the-shelf" therapeutic vaccine candidates for broad-spectrum immunotherapy purposes.
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Affiliation(s)
- Anastasia Goloudina
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Fabien Le Chevalier
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Pierre Authié
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Pierre Charneau
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Laleh Majlessi
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
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12
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Xiong X, Du Y, Liu P, Li X, Lai X, Miao H, Ning B. Unveiling EIF5A2: A multifaceted player in cellular regulation, tumorigenesis and drug resistance. Eur J Pharmacol 2025; 997:177596. [PMID: 40194645 DOI: 10.1016/j.ejphar.2025.177596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/28/2025] [Accepted: 04/02/2025] [Indexed: 04/09/2025]
Abstract
The eukaryotic initiation factor 5A2 gene (EIF5A2) is a highly conserved and multifunctional gene that significantly influences various cellular processes, including translation elongation, RNA binding, ribosome binding, protein binding and post-translational modifications. Overexpression of EIF5A2 is frequently observed in multiple cancers, where it functions as an oncoprotein. Additionally, EIF5A2 is implicated in drug resistance through the regulation of various molecular pathways. In the review, we describe the structure and functions of EIF5A2 in normal cells and its role in tumorigenesis. We also elucidate the molecular mechanisms associated with EIF5A2 in the context of tumorigenesis and drug resistance. We propose that the biological roles of EIF5A2 in regulating diverse cellular processes and tumorigenesis are clinically significant and warrant further investigation.
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Affiliation(s)
- Xifeng Xiong
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China; Guangzhou Institute of Burn Clinical Medicine, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Yanli Du
- Guangdong Medical University, Zhanjiang, 524023, Guangdong, China; Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Peng Liu
- Departments of Burn and Plastic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Xinye Li
- Guangdong Medical University, Zhanjiang, 524023, Guangdong, China; Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Xudong Lai
- Department of infectious disease, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Haixiong Miao
- Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China.
| | - Bo Ning
- Department of Neurosurgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China.
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13
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Wang X, Xu T, Ou A, Hu Z, Li M, Wu L, Jiang J, Wang L. Design, synthesis and in vitro and in vivo biological evaluation of matrine derivatives as efficient anticancer agents with the characteristics of endoplasmic reticulum stress induction and apoptosis activation. Bioorg Chem 2025; 160:108482. [PMID: 40273706 DOI: 10.1016/j.bioorg.2025.108482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/26/2025]
Abstract
Natural products have made significant contributions to the prevention and treatment of malignant tumors. However, natural products often suffer from low efficacy and potential toxicity. Therefore, modifying and optimizing lead compounds derived from natural products is a crucial strategy in drug development. In this study, we used matrine as an ideal lead compound and synthesized 27 matrine derivatives by incorporating indole structures with known antitumor activity. The antiproliferative effects of these derivatives were evaluated against human cancer cell lines (A549, HeLa, and Huh-7) and normal human liver cells (LO2). Compared to matrine, most of the derivatives exhibited superior antiproliferative activity. Notably, compound 9q showed significant antiproliferative activity against HeLa cells, with an IC50 value of 4.48 μM, demonstrating approximately 1500-fold greater potency than matrine (IC50 = 6756 μM). Further mechanistic studies revealed that compound 9q inhibited HeLa cell proliferation by modulating the expression of PI3K/AKT and Activating transcription factor 4 (ATF4) proteins. The upregulation of ATF4 promoted the expression of the key endoplasmic reticulum stress (ER stress) protein C/EBP homologous protein (CHOP). In the HeLa xenograft mouse model, compound 9q demonstrated significant anticancer efficacy. Therefore, compound 9q holds promise as a potential lead compound for the development of novel anticancer drugs.
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Affiliation(s)
- Xingdong Wang
- School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China
| | - Tingguo Xu
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Anqi Ou
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Zhouxing Hu
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Manqi Li
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Lichuan Wu
- School of Medicine, Guangxi University, Nanning 530004, China.
| | - Jun Jiang
- School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China.
| | - Lisheng Wang
- School of Medicine, Guangxi University, Nanning 530004, China.
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14
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Chen Z, Chen L, Li S, Xia P, Lam AKY, Qiao J, Liu Y, Qiao B. Integrated analysis of oral rinse-derived and plasma circulating tumour DNA for mutation profiling and outcome prediction with oral squamous cell carcinoma. NPJ Precis Oncol 2025; 9:183. [PMID: 40514434 DOI: 10.1038/s41698-025-00976-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 05/27/2025] [Indexed: 06/16/2025] Open
Abstract
This study evaluates the potential of oral rinse-derived and plasma circulating tumour DNA (ctDNA) in HPV-negative oral squamous cell carcinoma (OSCC), where early recurrence occurs in a significant proportion of patients, contributing to poor prognosis. Analysis of paired tissue, oral rinse, and plasma samples from 123 patients revealed ctDNA detection rates of 94.3% in oral rinse and 80.5% in plasma samples. Combined testing improved mutation detection sensitivity to 48.6%. A machine learning model integrating seven mutated genes (TP53, TERT, IKZF1, EP300, MYC, EGFR, PIK3CA) and clinical factors demonstrated robust prediction of recurrence (validation AUC: 0.854) and survival outcomes. Integration of pretreatment plasma ctDNA status further enhanced predictive performance. In longitudinal analysis, ctDNA detected recurrence approximately four months before clinical manifestation. These findings suggest that integrated ctDNA analysis offers improved mutation profiling and outcome prediction, potentially enabling earlier interventions in OSCC.
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Affiliation(s)
- Zhuo Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- School of Medicine & Dentistry, Griffith University, Southport, Australia
| | - Lihuang Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- School and Hospital of Stomatology, Weifang Medical University, Weifang, Shandong, China
| | - Shuaize Li
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Peng Xia
- Department of Anatomy and Histology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Alfred King-Yin Lam
- School of Medicine & Dentistry, Griffith University, Southport, Australia
- Pathology Queensland, Gold Coast University Hospital, Southport, QLD, Australia
| | - Jie Qiao
- Pilot Base of Food Microbial Resources Utilization of Hubei Province, School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Yi Liu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Bin Qiao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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15
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Hushmandi K, Farahani N, Einollahi B, Salimimoghadam S, Alimohammadi M, Liang L, Liu L, Sethi G. Deciphering molecular pathways in urological cancers: a gateway to precision therapeutics. J Adv Res 2025:S2090-1232(25)00395-9. [PMID: 40516913 DOI: 10.1016/j.jare.2025.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 06/02/2025] [Accepted: 06/05/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Urological cancers, including prostate, kidney, bladder, testicular, and penile cancers, pose a significant health challenge, particularly in their metastatic stages. Surgical interventions remain fundamental, but recent advancements in medical therapies like chemotherapy, immunotherapy, and targeted therapies have shown promise in improving patient outcomes. AIM OF REVIEW This review aims to explore the current landscape of targeted therapies in urological cancers, focusing on the role of key signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), mechanistic (mammalian) target of rapamycin (mTOR), growth factor-related mechanisms, c-Mesenchymal-epithelial transition factor (c-Met)/ hepatocyte growth factor (HGF), programmed cell death protein 1 and its ligand programmed death-ligand 1 (PD-1/PD-L1), and steroid hormone receptor pathways in tumor progression and therapeutic resistance. Key scientific concepts of review Dysregulation of pathways like PI3K/Akt and mTOR contributes to tumorigenesis, metastasis, and resistance to treatment, underscoring their relevance as therapeutic targets. Tyrosine kinase inhibitors and immune checkpoint inhibitors have demonstrated efficacy but face challenges such as intrinsic resistance and treatment-related toxicities. Integrating insights from signaling pathway research with clinical practice holds potential for developing more effective treatment paradigms, enhancing the efficacy of targeted therapies, and improving survival rates for patients with urological cancers.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Behzad Einollahi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran,Iran
| | - Liping Liang
- Guangzhou Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore 117600 Singapore, Singapore.
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16
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Doke R, Lokhande R, Chande K, Vinchurkar K, Prajapati BG. Recent advances in therapeutic strategies of Erdheim-Chester disease. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6407-6428. [PMID: 39836251 DOI: 10.1007/s00210-024-03769-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025]
Abstract
Erdheim-Chester disease (ECD) is a rare form of non-LCH characterized by excessive accumulation of histiocytes in various tissues, leading to significant morbidity. The estimated prevalence of ECD is low, with fewer than 1000 cases reported globally, yet it presents considerable clinical challenges due to its heterogeneous manifestations, which include bone pain, cardiovascular complications, and neurological symptoms. Traditional treatment approaches, primarily involving corticosteroids and chemotherapy, have limitations, including inconsistent responses and significant side effects. Recent advances in understanding the pathogenesis of ECD, particularly the role of the BRAF V600E mutation, have led to the exploration of novel therapeutic strategies, such as targeted BRAF inhibitors, MEK and mTOR inhibitors, and other immunotherapies, which offer promise in improving patient outcomes. The review further explores clinical manifestations, and radiographic features of Erdheim-Chester disease, and discusses treatment strategies, current clinical studies in the field of ECD. By integrating these aspects, this review aims to provide a thorough understanding of ECD and its evolving treatment landscape, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Rohit Doke
- Jaihind College of Pharmacy, Vadgaon Sahani, Pune, Maharashtra, 412401, India
| | - Rahul Lokhande
- Samarth Institute of Pharmacy, Belhe, Pune, Maharashtra, 412410, India
| | - Kalyani Chande
- Dr. DY Patil College of Pharmacy Akurdi, Pune, Maharashtra, 411044, India
| | - Kuldeep Vinchurkar
- Sandip Foundation's Sandip Institute of Pharmaceutical Sciences (SIPS), Nashik, Maharashtra, 422213, India.
| | - Bhupendra G Prajapati
- Department of Pharmaceutical Technology, Shree S K Patel College of Pharmaceutical Education and Research, Ganpat University, 384012, Mahesana, Gujarat, India.
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17
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Lyu Z, Yang J, Xu Z, Wang W, Cheng W, Tsui KL, Zhang Q. Predicting the risk of ischemic stroke in patients with atrial fibrillation using heterogeneous drug-protein-disease network-based deep learning. APL Bioeng 2025; 9:026104. [PMID: 40191603 PMCID: PMC11970939 DOI: 10.1063/5.0242570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/11/2025] [Indexed: 04/09/2025] Open
Abstract
Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug-protein-disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346-0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.
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Affiliation(s)
| | - Jiannan Yang
- Musketeers Foundation Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China
| | - Zhongzhi Xu
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Weilan Wang
- Centre for Healthy Longevity, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Kwok-Leung Tsui
- Department of Manufacturing, Systems, and Industrial Engineering, University of Texas, Arlington, Texas 76019, USA
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18
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Balla T. Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159615. [PMID: 40262701 PMCID: PMC12145240 DOI: 10.1016/j.bbalip.2025.159615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/08/2025] [Accepted: 04/18/2025] [Indexed: 04/24/2025]
Abstract
Phosphorylated products of phosphatidylinositol (PI), named Diphosphoinositide (DPI) and triphosphoinositide (TPI) were identified long time ago and found to exhibit high turnover rates based on their rapid 32P-phosphate labeling. The PI kinase activities that were responsible for their production were subsequently identified and found to be associated with different organelle membranes, including the plasma membrane. These activities were then linked with a certain group of cell surface receptors that activated phospholipase C enzymes to hydrolyze PI and used calcium or cGMP as a second messenger. This visionary concept was introduced in the seminal BBA review written by Robert Michell, exactly 50 years ago. The enzymology and functional diversity of PI 4-phosphate (PI4P) (the term that has replaced DPI) has since underwent an expansion that could not have been foreseen. In this review I will attempt to revisit this expansion with some historical reflections celebrating the 50th anniversary of the Michell review.
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Affiliation(s)
- Tamas Balla
- Section on Molecular Signal Transduction, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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19
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Kim ES. Molecular targets and therapies associated with poor prognosis of triple‑negative breast cancer (Review). Int J Oncol 2025; 66:52. [PMID: 40444482 PMCID: PMC12118953 DOI: 10.3892/ijo.2025.5758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Accepted: 05/07/2025] [Indexed: 06/02/2025] Open
Abstract
Triple‑negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of BC characterized by the absence of estrogen, progesterone and human EGFR2 receptors. This lack of receptors renders it unresponsive to standard targeted therapies. Despite advances made in understanding the molecular landscape of TNBC, its poor prognosis and high recurrence rates underscore the urgent need for innovative therapeutic approaches. This review explores the effects of key prognostic markers, such as Ki‑67, programmed cell death ligand 1, BRCA1/2 mutations, E‑cadherin loss and EGFR alterations. It also examines critical pathways, including the PI3K/AKT/mTOR and mutant p53 pathways, which are prerequisites for TNBC progression and therapy resistance, and discusses the therapeutic potential of directly targeting these key molecules and their associated signaling pathways. In addition, recent advances in targeted therapies were highlighted, such as immune checkpoint inhibitors, and the statuses of emerging strategies were presented, such as chimeric antigen receptor‑T cell therapy and small inhibitory RNA‑based treatments. Given the molecular heterogeneity of TNBC, the importance of precision medicine was also discussed and it was emphasized that this approach is becoming an increasingly critical aspect of personalized treatment strategies. Resistance to existing therapies presents a major challenge to the effective treatment of TNBC, and thus, the development of future therapeutic strategies requires technical innovations. By integrating these insights, this review aims to provide a comprehensive overview of current and future means of improving TNBC outcomes.
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Affiliation(s)
- Eun-Sook Kim
- College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea
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20
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Cazzola M, Page C, Rogliani P, Calzetta L, Matera MG. PI3K Inhibitors as Potential Therapeutic Agents for the Treatment of COPD with Associated Atherosclerosis. Drugs 2025; 85:741-753. [PMID: 40214902 PMCID: PMC12098434 DOI: 10.1007/s40265-025-02179-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 05/24/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) share a complex and multifactorial relationship characterized by overlapping risk factors, systemic inflammation, and intertwined pathophysiological mechanisms, with atherosclerosis emerging as a central inflammatory process connecting COPD and CVD, driven by systemic inflammation, oxidative stress, and endothelial dysfunction. While systemic inflammation is recognized as a critical link between these conditions, the precise pathways through which inflammation arises remain under investigation. There is therefore a need for therapeutic strategies to mitigate cardiovascular risks in patients with COPD. Among the pathways contributing to this interplay, the phosphoinositide 3-kinase (PI3K) signaling pathway has gained significant attention. Dysregulated PI3K signaling contributes to inflammation, oxidative stress, and endothelial dysfunction, which are key drivers of both COPD and CVD. Consequently, PI3K inhibitors have emerged as a promising therapeutic approach to mitigate inflammation and oxidative damage, offering a targeted strategy to address the shared pathological mechanisms underlying these diseases. A comprehensive understanding of the role of PI3K signaling and its inhibitors could facilitate the development of novel interventions to reduce cardiovascular risk in patients with COPD.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00131, Rome, Italy.
| | - Clive Page
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00131, Rome, Italy
| | - Luigino Calzetta
- Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
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21
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Fransén J, Frisk S, Ghaffarpour N. Lymphatic malformations revisited: genetics, clinics and future directions. Presse Med 2025:104293. [PMID: 40449789 DOI: 10.1016/j.lpm.2025.104293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 05/12/2025] [Indexed: 06/03/2025] Open
Abstract
The clinical management of lymphatic malformations presents challenges due to their rarity, variable presentation, and the potential for recurrence. Dissemination of the latest knowledge in lymphatic malformations is needed to streamline referral pathways and possibly improve patient outcomes. This paper provides a narrative review of the latest developments in aetiopathogenesis, diagnosis and management of lymphatic malformations. Multidisciplinary recommendations from the European Reference Network on Rare Multisystemic Vascular Diseases, Vascular Anomalies working group sets the basis for this review. A literature search was conducted to include the latest research based on authors' preferences. Understanding the aetiopathogenesis of lymphatic malformations is important, as new genetic insights can dictate management strategies. Advancements in diagnostics allow for better differentiation between malformation types and imaging of anatomical infiltrations, where treatment options differ and are more commonly multimodal. Further systematic studies are needed on larger study populations, such as prospective trials and meta-analyses, to improve evidence-based practice.
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Affiliation(s)
- Jian Fransén
- Department of Plastic and Maxillofacial Surgery, Karolinska University Hospital, Stockholm, Sweden.
| | - Sofia Frisk
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Génétique Humaine, de Duve Institute, UCLouvain, Bruxelles, Belgium; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Nader Ghaffarpour
- Department of Plastic and Maxillofacial Surgery, Karolinska University Hospital, Stockholm, Sweden
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22
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Tracy PD, Bopp E, Milner E, Garrido-Castro AC, Giordano A, Mayer EL, Tolaney SM, Tarantino P, Schlam I. Management of Metastatic Hormone Receptor-Positive Breast Cancer Beyond CDK4/6 Inhibitors. Curr Oncol Rep 2025:10.1007/s11912-025-01689-9. [PMID: 40434676 DOI: 10.1007/s11912-025-01689-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2025] [Indexed: 05/29/2025]
Abstract
PURPOSE OF REVIEW Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied. RECENT FINDINGS Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.
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Affiliation(s)
- Philip D Tracy
- Department of Hematology/Oncology, Tufts Medical Center, Boston, MA, 02111, USA
- Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Emily Bopp
- Department of Medicine, Tufts Medical Center, Boston, MA, 02111, USA
| | - Emily Milner
- Department of Medicine, Tufts Medical Center, Boston, MA, 02111, USA
| | - Ana C Garrido-Castro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Antonio Giordano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Erica L Mayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Paolo Tarantino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
- Department of Oncology and Onco-Hematology, University of Milan, Milan, 20122, Italy.
| | - Ilana Schlam
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
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23
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Xu W, Li X, He F, Zhao H, Wu J, Li M, Dai X, Li Y, Hu X, Li X, Cen J, Guo P, Duan S. Folate receptor-targeted pH-sensitive liposomes loaded with TGX-221 against prostate cancer by inhibiting PI3K/110β signaling. NANOSCALE ADVANCES 2025; 7:3267-3280. [PMID: 40212450 PMCID: PMC11979785 DOI: 10.1039/d5na00009b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/05/2025] [Indexed: 05/29/2025]
Abstract
Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility. Herein, by using folic acid-PEG-cholesterol semi-succinate (FA-PEG-CHEMS) as the targeting component, we developed a folate receptor-targeted pH-sensitive liposomal delivery system loaded with TGX221 (FA-Lip-TGX221) that could realize effective delivery and controlled release of drugs in the tumor. The prepared liposomes exhibited a uniform particle size and high stability. In addition, FA-Lip-TGX221 could be effectively internalized by PC-3 cells due to its ability to target folate receptors, thereby accumulating in tumor tissues. Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors.
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Affiliation(s)
- Weibo Xu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China
- Medical School, Henan University Kaifeng 475004 China
| | - Xiaohan Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Fujin He
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Han Zhao
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Jing Wu
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Mengyu Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaoying Dai
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Yanmin Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaojiao Hu
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaodong Li
- Medical School, Henan University Kaifeng 475004 China
| | - Juan Cen
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
- The First Affiliated Hospital of Henan University Kaifeng Henan 475004 PR China
| | - Peng Guo
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China
| | - Shaofeng Duan
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
- The First Affiliated Hospital of Henan University Kaifeng Henan 475004 PR China
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24
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Liu Z, Liao X, Zhao H, Ruan B, Jia F, He X, Long R. miR-29a-3p compositely regulates the COL6A6/PTEN-PI3K/Akt/CUX1 feedback loop to participate in the proliferation and invasion of pituitary adenomas. J Mol Histol 2025; 56:172. [PMID: 40419838 DOI: 10.1007/s10735-025-10436-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025]
Abstract
Pituitary adenoma (PA) is one of the most common intracranial tumors, and owing to its special biological morphology and behavior, there is currently no effective treatment. miRNAs play crucial roles as diagnostic indicators and targets for the treatment of numerous cancer types. The objective of this research was to explore how miR-29a-3p influences the development of PA. We collected 25 pairs of PA tissue and normal pituitary tissue, followed by the subcutaneous injection of 5 × 107 HP75 cells into the left axilla of nude mice, creating a heterotopic PA xenograft tumor model for experimental study. TtT/GF and HP75 cell proliferation and tumor growth in nude mice were assessed using CCK-8, Transwell, and immunohistochemistry tests. Western blotting, RT‒qPCR and RIP were used to detect the expression and interaction of related proteins and genes. The expression of miR-29a-3p was upregulated in PA. Knockdown of miR-29a-3p can inhibit the proliferation, invasion and migration of TtT/GF and HP75 cells and reduce the epithelial mesenchymal transformation (EMT) of these cells. Furthermore, reducing miR-29a-3p levels suppressed the expression of Ki-67 in the PA tissues of nude mice and slowed tumor growth. From a mechanistic standpoint, miR-29a-3p can target COL6A6 and PTEN. Knockdown of miR-29a-3p inhibits the PI3K/Akt/CUX1 signaling pathway through simultaneously increasing COL6A6 and PTEN expression, thus inhibiting the proliferation, invasion, migration and EMT of PA cells and alleviating the progression of PA. Conversely, CUX1 can promote the expression of miR-29a-3p through a positive feedback loop and accelerate the development of PA. Our study suggests that downregulating the expression of miR-29a-3p may be a new target for the treatment of PA.
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Affiliation(s)
- Zhuohui Liu
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Xiufu Liao
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Department of Otolaryngology, Chongqing General Hospital, Chongqing, 401147, Chongqing, China
| | - Hexiang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Biao Ruan
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Fengfeng Jia
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Xuzhi He
- Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, 400042, Chongqing, China.
| | - Ruiqing Long
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China.
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25
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Lin T, Liang T, Shen Y, Gao F. BACE1 Inhibition Protects Against Type 2 Diabetes Mellitus by Restoring Insulin Receptor in Mice. Int J Mol Sci 2025; 26:5100. [PMID: 40507910 PMCID: PMC12154494 DOI: 10.3390/ijms26115100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 06/16/2025] Open
Abstract
β-secretase 1 (BACE1), known for its role in amyloid-β production associated with Alzheimer's disease (AD), has also been suggested to be elevated in patients with Type 2 diabetes mellitus (T2DM). Notably, BACE1 could cleave the insulin receptor (InsR), leading to reduced InsR levels, which may impair insulin signaling and contribute to insulin resistance. Presently, we observed decreased InsR levels and impaired glucose disposal in the livers of mice with systemic overexpression of BACE1 (HUBC mice). This suggests that elevated BACE1 could contribute to insulin resistance by shedding membrane InsR. Additionally, mice fed a high-fat diet (HFD), a well-established model of T2DM, displayed increased BACE1 levels and decreased InsR. To further investigate whether inhibiting BACE1 could enhance insulin sensitivity and alleviate symptoms of diabetes, we treated HFD mice with the BACE1 inhibitor Elenbecestat. Remarkably, the administration of Elenbecestat restored InsR levels and improved their downstream signaling pathways, leading to increased insulin sensitivity and enhanced glucose tolerance. In summary, our findings suggest that inhibiting BACE1 can restore InsR expression and improve insulin-signaling sensitivity, ultimately resulting in enhanced diabetic phenotypes.
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Affiliation(s)
- Tingting Lin
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (T.L.); (T.L.)
| | - Ting Liang
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (T.L.); (T.L.)
| | - Yong Shen
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (T.L.); (T.L.)
- Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei 230001, China
| | - Feng Gao
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (T.L.); (T.L.)
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26
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Zhou H, Fu F, Huang R, Yu Q, Yan S, Lu J, Guo F, Ma C, Chen H, Liu L, Zhang Y, Jing X, Li F, Chen G, Li L, Lei T, Deng Q, Mei S, Chen C, Han J, Li R, Liao C. Prenatal Exome Sequencing for Fetal Macrocephaly: A Large Prospective Observational Cohort Study. Prenat Diagn 2025. [PMID: 40404351 DOI: 10.1002/pd.6818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 05/06/2025] [Accepted: 05/10/2025] [Indexed: 05/24/2025]
Abstract
OBJECTIVE To assess the diagnostic utility of exome sequencing (ES) in macrocephalic fetuses. METHODS Fetuses with macrocephaly (head circumference (HC) ≥ +2 SD) and negative chromosomal microarray results were included, who had available trio-ES data. Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC Z-scores, associated anomalies, and growth parameters. RESULTS Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio-ES. These diagnoses revealed that the variants predominantly affect key signaling pathways, including mTOR, RASopathies and Sotos syndrome. The detection rate was significantly higher in non-isolated compared to isolated macrocephaly cases (65.0%, 26/40 vs. 17.0%, 8/47; p < 0.001). The most frequent anomalies associated with genetic diagnoses included micromelia (100.0%, 14/14), megalencephaly (100.0%, 2/2), and ventriculomegaly (60.0%, 6/10). Subgroup analysis identified higher diagnostic yields in fetuses diagnosed before 32 gestational weeks, with HC Z-scores ≥ +3 SD, micromelia, and absence of large-for-gestational-age (LGA). CONCLUSIONS Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non-isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.
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Affiliation(s)
- Hang Zhou
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fang Fu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ruibin Huang
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Qiuxia Yu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shujuan Yan
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jianqin Lu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fei Guo
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Chunling Ma
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- The First Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Huanyi Chen
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Liyuan Liu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- The First Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Yongling Zhang
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiangyi Jing
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fucheng Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Guilan Chen
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Lushan Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Tingying Lei
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Qiong Deng
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shanshan Mei
- Obstetrical Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Chen Chen
- Respiratory Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jin Han
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ru Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Can Liao
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Wu J, Lai J, Zhao X, Wang Z, Zhang Y, Wang L, Su Y, He Y, Li S, Jiang Y, Han J. DeepCCDS: Interpretable Deep Learning Framework for Predicting Cancer Cell Drug Sensitivity through Characterizing Cancer Driver Signals. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2416958. [PMID: 40397390 DOI: 10.1002/advs.202416958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 04/18/2025] [Indexed: 05/22/2025]
Abstract
Accurate characterization of cellular states is the foundation for precise prediction of drug sensitivity in cancer cell lines, which in turn is fundamental to realizing precision oncology. However, current deep learning approaches have limitations in characterizing cellular states. They rely solely on isolated genetic markers, overlooking the complex regulatory networks and cellular mechanisms that underlie drug responses. To address this limitation, this work proposes DeepCCDS, a Deep learning framework for Cancer Cell Drug Sensitivity prediction through Characterizing Cancer Driver Signals. DeepCCDS incorporates a prior knowledge network to characterize cancer driver signals, building upon the self-supervised neural network framework. The signals can reflect key mechanisms influencing cancer cell development and drug response, enhancing the model's predictive performance and interpretability. DeepCCDS has demonstrated superior performance in predicting drug sensitivity compared to previous state-of-the-art approaches across multiple datasets. Benefiting from integrating prior knowledge, DeepCCDS exhibits powerful feature representation capabilities and interpretability. Based on these feature representations, we have identified embedding features that could potentially be used for drug screening in new indications. Further, this work demonstrates the applicability of DeepCCDS on solid tumor samples from The Cancer Genome Atlas. This work believes integrating DeepCCDS into clinical decision-making processes can potentially improve the selection of personalized treatment strategies for cancer patients.
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Affiliation(s)
- Jiashuo Wu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Jiyin Lai
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xilong Zhao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Ziyi Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yongbao Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Liqiang Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yinchun Su
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yalan He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Siyuan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Ying Jiang
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Junwei Han
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
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AlKharboush DF, Khayat MT, Jamal A, El-Araby ME, Awaji AA, Khan MI, Omar AM. Exploring a kinase inhibitor targeting PI3KCA mutant cancer cells. J Biomol Struct Dyn 2025:1-18. [PMID: 40390333 DOI: 10.1080/07391102.2025.2502137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 05/04/2024] [Indexed: 05/21/2025]
Abstract
The PI3K/mTOR signaling pathway is often disrupted in human cancers, with PI3Kα being one of the most mutated kinases. There has been considerable interest in developing small-molecule inhibitors aimed at blocking the mutant PI3Kα-driven phosphatidylinositol 3-kinase (PI3K) signaling pathway as a potential treatment for cancer. In this study, we describe our effort to identify a compound, phenylacetamide-1H-imidazol-5-one (KIM-161), from our in-house oncogenic kinase-targeting inhibitors. KIM-161 showed excellent anti-proliferative activities at sub-nanomolar concentrations, primarily against mutant PI3Kα breast cancer cell lines, when compared with wild-type PI3Kα breast cancer cell lines, producing both dose- and time-dependent effects with an IC50 range of 1.42 - 0.064 µM. Next, we observed that KIM-161 was able to induce ROS production by modulating breast cancer metabolism, suggesting its broad effects on mutant PI3Kα regulated downstream pathways. We also computationally analyzed the binding interactions between KIM-161 and PI3K-alpha (PDB ID: 8EXL). Molecular docking showed that KIM-161 had a docking score of -7.44 Kcal/mol, compared to the reference compound, which had a docking score of -7.67 Kcal/mol. Moreover, molecular dynamics simulation studies demonstrated that the PI3Ka-KIM-161 complex remained stable throughout the 100 ns simulation, when compared to the PI3Ka complex with the co-crystallized inhibitor. These findings present KIM-161 as a promising lead, providing valuable insights into treatment approaches and resistance mechanisms associated with PI3K inhibitors in specific PIK3CA-mutant cancer subtypes.
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Affiliation(s)
- Dana F AlKharboush
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maan T Khayat
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alam Jamal
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Moustafa E El-Araby
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Aeshah A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Imran Khan
- Research Center, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Abdelsattar M Omar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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29
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Wang H, Zhu J, Wang H, Zheng W, Wang L, Zhu J, Wang Z, Du Q. The role of FAM111B in the malignant progression and molecular regulation of human glioma through the PI3K/Akt pathway. Chin Neurosurg J 2025; 11:9. [PMID: 40390043 PMCID: PMC12087166 DOI: 10.1186/s41016-025-00395-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/14/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Gliomas represent the most prevalent primary neoplasm in the adult central nervous system. Despite advancements in therapeutic modalities, such as surgical intervention, radiotherapy, chemotherapy, and tumor treatment, the 5-year survival rate of glioma patients remains low. Therefore, there is an urgent need to develop additional treatment methods. Recent studies have suggested that FAM111B is involved in DNA repair, cell cycle regulation, and apoptosis. FAM111B mutations and overexpression are related to cancer. METHODS We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases. Moreover, overexpression of FAM111B was associated with shorter overall survival, and disease-specific survival and tended to increase with disease stage progression. Cellular experiments confirmed these results. These results suggest that overexpression of FAM111B promotes the proliferation, migration, and invasion of glioma cells, whereas the knockdown of FAM111B inhibits these activities. We also found that FAM111B regulated glioma cell proliferation, migration, and invasion via the PI3K/AKT pathway. RESULTS FAM111B is capable of enhancing the proliferation, invasion, and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway. CONCLUSIONS This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation, migration, and invasion of glioma cells. The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway. FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.
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Affiliation(s)
- Heng Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Junrou Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Haiyang Wang
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Wenhao Zheng
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Linjie Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Jinhao Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Zheng Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Quan Du
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
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Wang Y, Yu DH, Quan W, Lan T, Tang F, Ma C, Li ZQ, Hong K, Wang ZF. Marine-derived fungal metabolite MHO7 promotes glioblastoma cell apoptosis as a novel Akt inhibitor by targeting membrane phosphatidylethanolamine. Int Immunopharmacol 2025; 155:114656. [PMID: 40233448 DOI: 10.1016/j.intimp.2025.114656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/17/2025]
Abstract
Temozolomide (TMZ) chemoresistance is a major challenge in the management of glioblastoma (GBM). Marine-derived fungal metabolites are a significant source of potential chemotherapeutic candidates. This study aimed to investigate the cytotoxic effect of MHO7 (6-epi-ophiobolin G) on GBM cells. MHO7 inhibited GBM cell proliferation and promoted apoptosis, accompanied by a reduction in Akt activity and membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) content. We verified that MHO7 could react with phosphatidylethanolamine (PE), the second most abundant phospholipid in the plasma membrane, to form a covalent adduct. Pre-incubation with exogenous PE significantly alleviated the pro-apoptotic effect of MHO7, with a concomitant increase in Akt activity and membrane PIP2 and PIP3 content. Since binding to PIP3 is a key step in Akt activation, our results indicate that MHO7 can function as a novel Akt inhibitor. Additionally, MHO7 has a synergistic pro-apoptotic effect with TMZ, and TMZ-resistant GBM cells remain sensitive to MHO7. MHO7 had little cytotoxicity against normal neuronal cells. The anti-growth effect of MHO7 was also observed in an orthotopic glioma mice model. Therefore, MHO7 is a promising chemotherapeutic agent for GBM. This study also indicated that membrane lipid-targeted therapy may be a novel and effective strategy for tumor treatment.
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Affiliation(s)
- Yi Wang
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Dong-Hu Yu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Quan
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Tian Lan
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Feng Tang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chao Ma
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhi-Qiang Li
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Kui Hong
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
| | - Ze-Fen Wang
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
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31
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Sahm F, Bertero L, Brandner S, Capper D, Goldbrunner R, Jenkinson MD, Kalamarides M, Lamszus K, Albert NL, Mair MJ, Berghoff AS, Mawrin C, Wirsching HG, Maas SLN, Raleigh DR, Reifenberger G, Schweizer L, Suwala AK, Tabatabai G, Tabouret E, Short S, Wen PY, Weller M, Le Rhun E, Wesseling P, van den Bent M, Preusser M. European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection. Neuro Oncol 2025; 27:869-883. [PMID: 39577862 PMCID: PMC12083233 DOI: 10.1093/neuonc/noae253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Indexed: 11/24/2024] Open
Abstract
Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.
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Affiliation(s)
- Felix Sahm
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sebastian Brandner
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David Capper
- German Cancer Consortium (DKTK), partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Roland Goldbrunner
- Department of Neurosurgery, University Hospital Cologne, Cologne, Germany
| | - Michael D Jenkinson
- Department of Neurosurgery, University of Liverpool and Walton Centre, Liverpool, UK
| | - Michel Kalamarides
- Department of Neurosurgery, Pitie-Salpetriere Hospital, AP-HP Sorbonne Université, Paris, France
| | - Katrin Lamszus
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathalie L Albert
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Maximilian J Mair
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Anna S Berghoff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Christian Mawrin
- Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany
| | - Hans-Georg Wirsching
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Sybren L N Maas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - David R Raleigh
- Departments of Radiation Oncology, Neurological Surgery, and Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
| | - Leonille Schweizer
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Abigail K Suwala
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Ghazaleh Tabatabai
- Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, DKTK partner site Tübingen, University of Tübingen, Germany
| | - Emeline Tabouret
- Aix-Marseille Universite, APHM, CNRS, INP, Institut Neurophysiopathol, GlioME Team, Plateforme PETRA, CHU Timone, Service de Neurooncologie, Marseille, France
| | - Susan Short
- Department of Oncology, Leeds Institute of Medical Research at St James’s Hospital, Leeds, UK
| | - Patrick Y Wen
- Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Michael Weller
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Emilie Le Rhun
- Department of Medical Oncology and Hematology, Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands
| | - Martin van den Bent
- The Brain Tumor Center at Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Chu MQ, Zhang TJ, Yang Q, Feng Y, Lu C, Ji YH, Qian J, Zhou JD. Successful treatment of an elderly patient with relapsed/refractory angioimmunoblastic T-cell lymphoma with the PI3Kδ inhibitor linperlisib: a Case Report. Front Pharmacol 2025; 16:1554501. [PMID: 40444052 PMCID: PMC12119530 DOI: 10.3389/fphar.2025.1554501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/21/2025] [Indexed: 06/02/2025] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL), a highly aggressive peripheral T-cell lymphoma (PTCL), carries a poor prognosis in elderly patients due to frequent relapse and limited salvage options after multiline therapy. We present the case of an 80-year-old woman with relapsed/refractory (R/R) AITL who relapsed after CHOP and exhibited resistance to the following sequential therapies: second-line chidamide plus COP and third-line chidamide with mitoxantrone hydrochloride liposome. Molecular analysis revealed DNMT3A and IDH2 mutations, reflecting disease complexity. Salvage therapy with linperlisib, a selective PI3Kδ inhibitor, combined with gemcitabine/oxaliplatin induced sustained partial remission, followed by linperlisib maintenance. The regimen demonstrated exceptional safety, with no grade ≥2 toxicities, even in this frail population. This case highlights the dual role of linperlisib as an effective and well-tolerated therapy for elderly R/R AITL patients who have exhausted prior lines. By precisely targeting PI3Kδ, our findings offer critical real-world evidence to address the unmet need for safe salvage strategies in this vulnerable population.
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Affiliation(s)
- Ming-Qiang Chu
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
| | - Ting-Juan Zhang
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Qian Yang
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
| | - Yuan Feng
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
| | - Chao Lu
- Department of Medical Imaging, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yong-Hui Ji
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
| | - Jun Qian
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
| | - Jing-Dong Zhou
- Department of Hematology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, China
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Liu Y, Wu Q, Shao J, Mei Y, Zhang J, Xu Q, Mao L. The NLRP3 inflammasome: a therapeutic target of phytochemicals in treating atherosclerosis (a systematic review). Front Immunol 2025; 16:1568722. [PMID: 40443656 PMCID: PMC12119316 DOI: 10.3389/fimmu.2025.1568722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/22/2025] [Indexed: 06/02/2025] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease characterized by the gradual accumulation of plaques in arterial walls, with its pathogenesis remaining incompletely understood. Recent studies have highlighted that development of AS is closely associated with the aberrant activation of the NLRP3 inflammasome in the arteries. Inhibition of the NLRP3 inflammasome by natural products and formulae derived from Chinese herbal medicines (CHMs) has been shown to alleviate AS-associated pathologies. However, therapies that effectively and safely target the NLRP3 inflammasome remain limited. This review aims to summarize the key discoveries from recent studies on the effects of these natural products and formulae on the NLRP3 inflammasome in the context of AS treatment. A comprehensive literature search was conducted on databases such as PubMed/MEDLINE up to January 2025, yielding 38 eligible studies. Our analysis indicates that certain therapies can effectively prevent arterial inflammation in animal models by targeting multiple pathways and mechanisms related to the NLRP3 inflammasome. This review summarizes the primary findings of these studies, focusing on the therapeutic effects and underlying mechanisms of action. Based on these insights, we propose future strategies to enhance the efficacy, specificity, and safety of existing natural products and formulae for AS treatment. Additionally, this study offers a perspective for future research that may enhance our understanding of the roles and the mechanisms of CHM-derived phytochemicals and formulae in regulating the NLRP3 inflammasome and treating AS.
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Affiliation(s)
- Yongchao Liu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Qianyi Wu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Jing Shao
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Youmin Mei
- Department of Periodontology, Nantong Stomatological Hospital, Nantong, China
| | - Jie Zhang
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Qiuyun Xu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Liming Mao
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China
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Zhou Y, Wang F, Feng S, Li M, Zhu M. USP39 promote post-translational modifiers to stimulate the progress of cancer. Discov Oncol 2025; 16:749. [PMID: 40358671 PMCID: PMC12075731 DOI: 10.1007/s12672-025-02573-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.
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Affiliation(s)
- Yuli Zhou
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Fang Wang
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Siren Feng
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Mengsen Li
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570216, China.
| | - Mingyue Zhu
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
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35
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Tyrakis PA, Kampjut D, Steele GF, Lindström HJG, Chirnomas D, Hopkins BD, Goncalves MD, Mukherjee S, Cantley LC, Maddocks ODK. Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models. Br J Cancer 2025:10.1038/s41416-025-03035-z. [PMID: 40360883 DOI: 10.1038/s41416-025-03035-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/11/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND While PI3K/AKT/mTOR signalling plays a critical role in cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation. METHODS Using models of endometrial and breast cancer, we evaluated the efficacy of a multi-node PI3K/AKT/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 inhibitor sapanisertib, PI3Kα inhibitor serabelisib and an insulin-supressing diet. Pathway signalling inhibition versus a range of single-node inhibitors was measured via S6, AKT and 4E-BP1 phosphorylation. RESULTS The serabelisib-sapanisertib combination more effectively suppressed PI3K/AKT/mTOR pathway signalling, particularly 4E-BP1, than single-node inhibitors, including alpelisib, capivasertib, inavolisib, everolimus and mutant-specific PI3K inhibitors RLY-2608 and STX-478. Serabelisib plus sapanisertib combined effectively with a range of other therapeutics, such as chemotherapies, hormone targeted therapies and CDK4/6 inhibitors. In xenograft models, sapanisertib, serabelisib plus paclitaxel/insulin supressing diet achieved complete inhibition of tumour growth/tumour regression. CONCLUSION Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours.
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Affiliation(s)
- Petros A Tyrakis
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Domen Kampjut
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Georgina F Steele
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - H Jonathan G Lindström
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Deborah Chirnomas
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Benjamin D Hopkins
- Englander Institute for Precision Medicine, Meyer Cancer Center, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | | | - Siddhartha Mukherjee
- Department of Medicine, Columbia University Irving Cancer Research Center, Columbia University, New York, NY, 10032, USA
| | - Lewis C Cantley
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Oliver D K Maddocks
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
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36
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Liu L, Wuyun T, Sun X, Zhang Y, Cha G, Zhao L. Therapeutic efficacy of TMTP1-modified EVs in overcoming bone metastasis and immune resistance in PIK3CA mutant NSCLC. Cell Death Dis 2025; 16:367. [PMID: 40328748 PMCID: PMC12055990 DOI: 10.1038/s41419-025-07685-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 05/08/2025]
Abstract
Non-small cell lung cancer (NSCLC) with PIK3CA mutations demonstrates significant challenges in treatment due to enhanced bone metastasis and immune checkpoint resistance. This study investigates the efficacy of tumor-targeting peptide 1-modified cancer stem cell-derived extracellular vesicles (TMTP1-TSRP-EVs) in reshaping the tumor microenvironment and reversing immune checkpoint resistance in NSCLC. By integrating TMTP1-TSRP into EVs, we aim to specifically deliver therapeutic agents to NSCLC cells, focusing on inhibiting the PI3K/Akt/mTOR pathway, a crucial driver of oncogenic activity and immune evasion in PIK3CA-mutated cells. Our comprehensive in vitro and in vivo analyses show that TMTP1-TSRP-EVs significantly inhibit tumor growth, reduce PD-L1 expression, and enhance CD8+ T cell infiltration, effectively reversing the immune-suppressive microenvironment. Moreover, the in vivo models confirm that our approach not only suppresses bone metastases but also overcomes primary resistance to immune checkpoint inhibitors by modulating the expression of key immunological markers. These findings suggest that targeted delivery of TMTP1-TSRP-EVs could provide a novel therapeutic strategy for treating PIK3CA-mutant NSCLC, offering significant improvements over traditional therapies by directly targeting the molecular pathogenesis of tumor resistance and metastasis. Molecular Mechanisms Reshaping the TME to Halt PI3K-Mutant Bone Metastasis of NSCLC and Overcoming Primary ICI Resistance. (Created by BioRender).
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Affiliation(s)
- Liwen Liu
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tanghesi Wuyun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Sun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Zhang
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Geqi Cha
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ling Zhao
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China.
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37
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Cartwright D, Kidd AC, Ansel S, Ascierto ML, Spiliopoulou P. Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance? Int J Mol Sci 2025; 26:4393. [PMID: 40362630 PMCID: PMC12072740 DOI: 10.3390/ijms26094393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.
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Affiliation(s)
- Douglas Cartwright
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Andrew C. Kidd
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Sonam Ansel
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Maria Libera Ascierto
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
| | - Pavlina Spiliopoulou
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
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Tiwari V, Kamboj A, Sheoran B, Chaudhary E, Yadav M, Kumari A, Krishania M, Ali U, Tiwari A, Garg M, Bhatnagar A. Anthocyanin-rich black wheat as a functional food for managing type 2 diabetes mellitus: a study on high fat diet-streptozotocin-induced diabetic rats. Food Funct 2025; 16:3273-3295. [PMID: 39688703 DOI: 10.1039/d4fo05065g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Background: Type 2 Diabetes Mellitus (T2DM) is associated with insulin resistance, hyperglycemia, and hyperlipidemia. Anthocyanins, which are natural antioxidants, have been reported to manage T2DM-related complications. However, the potential of anthocyanin-rich black wheat as a functional food for managing diabetes remains unexplored. Aim: This study aimed to investigate the effects of anthocyanin-rich black wheat on glucose metabolism, insulin sensitivity, lipid profile, oxidative stress, inflammation, and organ protection in high fat diet-streptozotocin (HFD-STZ) induced T2DM rats. Methods: T2DM was induced in rats using HFD-STZ. The rats were fed with either white wheat or anthocyanin-rich black wheat chapatti. Glucose metabolism, insulin sensitivity, lipid profile, antioxidant enzymes, inflammatory markers, and glucose transporters were assessed. Histopathological analysis of the liver, kidneys, and spleen was performed. Results: Compared to white wheat chapatti, black wheat chapatti exhibited higher α-amylase and α-glucosidase inhibitory activities. Black wheat chapatti consumption significantly reduced blood glucose and HbA1c levels, and improved insulin sensitivity, oral glucose tolerance, and insulin tolerance. Antioxidant enzyme (superoxide dismutase and catalase) activities were enhanced. Atherogenic dyslipidemia was attenuated, with improved high-density lipoprotein cholesterol levels. Inflammatory markers (TNF-α, IL-1β, leptin, resistin and cortisol) were reduced, while adiponectin (Acrp-30) levels increased. Black wheat chapatti activated adiponectin-AMPK and PI3K-AKT pathways, upregulating glucose transporters (GLUT-2 and GLUT-4). Histopathology revealed protective effects on the liver, kidneys, and spleen. Conclusions: Anthocyanin-rich black wheat chapatti ameliorates insulin resistance and associated complications in HFD-STZ-induced T2DM rats. It modulates key signaling pathways and glucose transporters, demonstrating its potential as a functional food for managing T2DM and its complications.
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Affiliation(s)
- Vandita Tiwari
- Department of Biochemistry, Panjab University, Chandigarh, India
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Akhil Kamboj
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Bhawna Sheoran
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Era Chaudhary
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Mona Yadav
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Anita Kumari
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Meena Krishania
- Center of Innovative and Applied Bioprocessing, Mohali, Punjab, India
| | - Usman Ali
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Apoorv Tiwari
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Monika Garg
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
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Yan H, Zhao L, He K, Liu H, Zhang C, Liu Q, Song K, Yang H, Xu T, Yang S. EPO Enhances Adaptation to Hypoxic Environment in the Freshwater Teleost ( Micropterus salmoides) through the PI3K/AKT Pathway. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:8402-8416. [PMID: 40239033 DOI: 10.1021/acs.est.5c00093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Hypoxia has become one of the most common environmental stress events in the life history of aquatic organisms due to accelerated global warming. Exploring the adaptation mechanisms of aquatic organisms in hypoxic environments is important to deepen our understanding of environmental toxicology and to design breeding programs. In this study, the largemouth bass Micropterus salmoides exhibited greater hypoxic adaptability after 4 weeks of intermittent hypoxic exposure (IHE), with the O2 tension for loss of equilibrium decreased from 1.17 ± 0.20 to 0.66 ± 0.10 mg/L. Combined transcriptomics, biochemical detection, and immunostaining results revealed that the hypoxia-tolerant phenotype driven by IHE was strongly correlated with the activation of erythropoietin (EPO). EPO promoted phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling to alleviate hepatic damage under acute hypoxic exposure (AHE) by selectively regulating the expression of genes related to antioxidant defense, antiapoptosis, and cell proliferation, which plays an important role in regulating hypoxic adaptation. The inhibition of EPO impaired cell survival in hypoxic environments, but intervention with the PI3K agonist 740 Y-P reversed this process. This novel finding provides insights into exploring how aquatic organisms cope with the challenges of hypoxia under increasing environmental risks.
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Affiliation(s)
- Haoxiao Yan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Liulan Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Kuo He
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Hao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Chengxian Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Qiao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Kaige Song
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Hangyu Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Tianjun Xu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Song Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
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40
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Zhou Y, Zhang X, Yin H. A Site-Specific Photo-Crosslinking Proteomics Approach Provides Insights into Noncanonical Pyroptotic Caspase-4 Substrates. Angew Chem Int Ed Engl 2025; 64:e202501535. [PMID: 40070324 DOI: 10.1002/anie.202501535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 03/09/2025] [Accepted: 03/11/2025] [Indexed: 03/26/2025]
Abstract
Inflammatory caspases (1/4/5) are key effectors in the process of pyroptosis by cleaving and activating the pore-forming protein gasdermin D (GSDMD). Unlike other caspases whose substrates have been well characterized, the substrates for caspase-4, which mediate noncanonical pyroptosis, remain poorly understood. Here, we combined noncanonical amino acids, photo-crosslinking, and proteomics to profile caspase-4 substrates, enabling the capture of transient protein interactions with activated caspase-4. A set of new substrates were identified by photo-crosslinking mass spectrometry, revealing the signaling pathway and biological process affected by pyroptosis. Notably, we found that AKT1 is cleaved at D108, which removes its autoinhibition and membrane localization domain, resulting in the release of activated AKT1. Our results also showed the precursor of caspase-5/12 could be cleaved by caspase-4 to form the p20/p10 active conformation, uncovering a previously unrecognized pyroptotic caspase cascade. Overall, this study presents an approach for identifying caspase-4 substrates and offers further understanding of noncanonical pyroptosis.
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Affiliation(s)
- Yi Zhou
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xinyu Zhang
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Hang Yin
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
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41
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Li Y, Sun Y, Yu K, Li Z, Miao H, Xiao W. Keratin: A potential driver of tumor metastasis. Int J Biol Macromol 2025; 307:141752. [PMID: 40049479 DOI: 10.1016/j.ijbiomac.2025.141752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/19/2025]
Abstract
Keratins, as essential components of intermediate filaments in epithelial cells, play a crucial role in maintaining cell structure and function. In various malignant epithelial tumors, abnormal keratin expression is frequently observed and serves not only as a diagnostic marker but also closely correlates with tumor progression. Extensive research has demonstrated that keratins are pivotal in multiple stages of tumor metastasis, including responding to mechanical forces, evading the immune system, reprogramming metabolism, promoting angiogenesis, and resisting apoptosis. Here we emphasize that keratins significantly enhance the migratory and invasive capabilities of tumor cells, making them critical drivers of tumor metastasis. These findings highlight the importance of targeting keratins as a strategic approach to combat tumor metastasis, thereby advancing our understanding of their role in cancer progression and offering new therapeutic opportunities.
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Affiliation(s)
- Yuening Li
- Army Medical University, Chongqing, China
| | - Yiming Sun
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Kun Yu
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Zhixi Li
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
| | - Hongming Miao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China; Jinfeng Laboratory, Chongqing, China.
| | - Weidong Xiao
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
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42
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Alharbi S, Merkle S, Hammill AM, Waters AM, Le Cras TD. RAS Pathway Mutations and Therapeutics in Vascular Anomalies. Pediatr Blood Cancer 2025; 72:e31605. [PMID: 39984187 DOI: 10.1002/pbc.31605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/30/2024] [Accepted: 02/02/2025] [Indexed: 02/23/2025]
Abstract
Vascular anomalies (VAs) are a diverse group of vascular tumors and vascular malformations (VMs). VMs are characterized by abnormal vessel development, overgrowth, and dysfunction. Coagulopathy, edema, and effusions can cause severe morbidity and mortality in children and adults with these diseases. Germline or somatic mutations in the RAS/RAF/MAPK pathway have been identified in multiple types of VAs. RAS genes (KRAS, NRAS, and HRAS) are small GTPase proteins that play an important role in normal development and cell function. In healthy cells, RAS proteins cycle between GDP (inactive) and GTP (active) states that regulate important functions such as proliferation, migration, and survival. "Hot spot" mutations in codons 12, 13, or 61 of RAS genes are found in multiple tumor types and VAs. RAS mutations often cause excessive MAP kinase signaling, driving unchecked cell proliferation. In this review, we discuss the different RAS pathway mutations discovered in VAs and the role that these may play using insights from cell and animal models. Current therapies targeting RAS pathways are presented. In the future, a better understanding of the role of RAS pathway mutations may advance therapeutic strategies for people with VAs.
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Affiliation(s)
- Sara Alharbi
- Cancer and Cell Biology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Svatava Merkle
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Adrienne M Hammill
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Andrew M Waters
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Timothy D Le Cras
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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43
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Zhang ZL, Xu HN, Gong CM, Li YZ, Song XM, Li YM, Zhang DD, Wang R. Microorganism-Derived Bisindole Alkaloids With Anticancer Potential and Their Mechanisms: A Comprehensive Review. Chem Biodivers 2025; 22:e202402398. [PMID: 39714457 DOI: 10.1002/cbdv.202402398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 12/24/2024]
Abstract
Bisindole alkaloids constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the last six decades, researchers have isolated 425 microorganism-derived bisindole alkaloids (MDBAs). Among them, 187 MDBAs have demonstrated anticancer properties against various in vitro cancer cell lines, primarily by impeding the cell cycle, restraining cell proliferation, and inducing apoptosis and autophagy. These effects are mediated by regulating key targets and signaling pathways such as hypoxia-inducible factor (HIF)-1, MAPK, and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR. This review provides a comprehensive examination of the sources, chemical diversity, and anticancer properties of these compounds. Furthermore, it summarizes the structure-activity relationship (SAR), druggability, and the mechanisms underlying MDBAs' anticancer effects. Ultimately, this article aims to furnish a thorough overview of the advancements in the investigation of microorganism-derived bisindole alkaloids for their continued development and utilization.
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Affiliation(s)
- Zi-Long Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Hao-Nan Xu
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Chuan-Ming Gong
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yu-Ze Li
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Xiao-Mei Song
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yi-Ming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Dong-Dong Zhang
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Rui Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
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Kamiki J, Gorgulho CM, Lérias JR, Maeurer MJ. Mucosal-associated invariant T-cells in pulmonary pathophysiology. Curr Opin Pulm Med 2025; 31:202-210. [PMID: 40104908 PMCID: PMC11957436 DOI: 10.1097/mcp.0000000000001163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
PURPOSE OF REVIEW Mucosal-associated invariant T-cells (MAIT) have been associated with lung cancer and pulmonary infections. The treatment of patients with cancer or infections includes host-directed therapies (HDTs). MAIT play a role in shaping the 'milieu interne' in cancer and infections and this review addresses the biology of MAIT in pulmonary pathophysiology. RECENT FINDINGS MAIT represent an attractive target for therapy in pulmonary malignancies and infections. T-cells are often difficult to exploit therapeutically due to the diversity of both T-cell receptor (TCR) repertoire and its ligandome. MAIT-cells are restricted by the major histocompatibility complex class I-related gene protein (MR1) that presents nondefined tumor-associated targets, bacterial products, vitamin and drug derivates. Due to their plasticity in gene expression, MAIT are able to conversely switch from IFN-γ to IL-17 production. Both cytokines play a key role in protective immune responses in infections and malignancies. MAIT-derived production of interleukin (IL)-17/TGF-β shapes the tumor micro-environment (TME), including tissue re-modelling leading to pulmonary fibrosis and recruitment of neutrophils. MAIT contribute to the gut-lung axis associated with clinical improved responses of patients with cancer to checkpoint inhibition therapy. MAIT are at the crossroad of HDTs targeting malignant and infected cells. Clinical presentations of overt inflammation, protective immune responses and tissue re-modeling are reviewed along the balance between Th1, Th2, Th9, and Th17 responses associated with immune-suppression or protective immune responses in infections. SUMMARY MAIT shape the TME in pulmonary malignancies and infections. Drugs targeting the TME and HDTs affect MAIT that can be explored to achieve improved clinical results while curbing overt tissue-damaging immune responses.
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Affiliation(s)
- Jéssica Kamiki
- ImmunoTherapy/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Lisbon, Portugal
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Wang Z, Wang S, Liu Y, Wang X, Li W, Qi H, You H. 6PPD induces apoptosis and autophagy in SH-SY5Y cells via ROS-mediated PI3K/AKT/mTOR pathway: In vitro and in silico approaches. Toxicology 2025; 513:154091. [PMID: 39983890 DOI: 10.1016/j.tox.2025.154091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/04/2025] [Accepted: 02/16/2025] [Indexed: 02/23/2025]
Abstract
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), an extensively employed antioxidant in rubber materials, is considered as an emerging contaminant. 6PPD was proven to have potential neurotoxicity, which poses risks to human health. However, the research on its neurotoxicity is still limited. This work explored the neurotoxicity of 6PPD to SH-SY5Y cells and in-depth mechanisms with a combination of in vitro and in silico approaches. Our results indicated that 6PPD could reduce cell viability and cause oxidative damage by increasing reactive oxygen species (ROS) accumulation and altering the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). 6PPD induced neuronal apoptosis of mitochondrial pathway and autophagy dysfunction, as characterized by the increased expressions of Cleaved caspase-3, Bax/Bcl-2, Beclin-1, LC3-II/I, and P62. 6PPD downregulated the expression of PI3K, p-AKT, and p-mTOR, while the PI3K inhibitor suppressed PI3K/AKT/mTOR pathway and promoted both apoptosis and autophagy, indicating that PI3K/AKT/mTOR pathway was involved in 6PPD-induced apoptosis and autophagy. The inhibition of this pathway was attributed to ROS accumulation in SH-SY5Y cells. Molecular docking analysis further revealed that 6PPD exhibits strong binding affinity to PI3K, AKT, and mTOR protein molecules, which could effectively interfere with downstream signaling pathways. These findings enrich the understanding of 6PPD-induced neurotoxicity and contribute to the evaluation of ecological risks associated with 6PPD.
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Affiliation(s)
- Ziwei Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Shutao Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China.
| | - Yingying Liu
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Xingyu Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Wanlun Li
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Hong Qi
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Hou You
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
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Che X, Shang X, WeiXu, Xing M, Wei H, Li W, Li Z, Teng X, Geng L. Selenium-enriched Lactiplantibacillus plantarum alleviates alkalinity stress-induced selective hepatic insulin resistance in common carp. Int J Biol Macromol 2025; 305:141204. [PMID: 39986514 DOI: 10.1016/j.ijbiomac.2025.141204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/18/2024] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
Carbonate alkalinity is one of the primary factors limiting saline-alkaline water aquaculture, and high alkalinity can lead to respiratory alkalosis, which is hazardous to fish health. Selenium (Se) and Lactiplantibacillus plantarum (L. plantarum) can be used for the biosynthesis of organic selenium (selenium-enriched Lactiplantibacillus plantarum: SL), which has low toxicity, high bioavailability, and the promotion of metabolism. Additionally, it can be used as a feed additive in aquaculture. In the present study, we established a model of chronic alkalinity stress in common carp and added SL to the feed. We found that alkalinity stress can cause severe hepatic dysfunction in common carp, as well as disrupt the intestinal barrier, further contributing to the translocation of enterogenous lipopolysaccharides through portal circulation and exacerbating liver injury. SL alleviated glucose-lipid metabolism abnormalities of the liver while reducing serum LPS levels and reduction of enterogenous LPS translocation to the liver, thus significantly reducing the degree of intestinal villi damage, hepatocyte vacuolisation, and nuclear damage. The significantly increased activities of SOD, GSH-Px, CAT, and T-AOC revealed that SL improved the antioxidant capacity of common carp. SL inhibited the alkalinity stress-induced overexpression of genes related to lipid synthesis and gluconeogenesis by modulating the P13K/Akt/FoxO1 signalling pathway, thus alleviating selective hepatic insulin resistance. SL attenuated the inflammatory response by modulating the mRNA expression levels of IL-7, IL-6, TNF-α and IL-10. In addition, apparent increase in the abundance of pathogenic bacteria (Brevinema, Bosea, Luteolibacter, and Vibrio) and apparent reduction in the abundance of beneficial bacteria (Cetobacterium, ZOR0006, and Shewanella) were closely related to the hepato-intestinal circulation process in carp exposed to alkalinity stress. SL regulated the hepato-intestinal circulation, reduced the abundance of Brevinema, Bosea, Luteolibacter, and Vibrio, increased the abundance of Cetobacterium, ZOR0006, and Shewanella, alleviated alkalinity stress-induced damage to intestinal microvilli (villus height and width), and significantly restored normal liver and intestinal functions. This study reveals the physiological regulatory mechanism by which Se-enriched L. plantarum through liver-intestinal axis alleviates alkalinity stress-induced hepatic insulin resistance and may provide new ideas and a theoretical basis for protecting against alkalosis and treating insulin resistance.
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Affiliation(s)
- Xinghua Che
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Xinchi Shang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China; College of Life Science, Northeast Agricultural University, Harbin 150036, China
| | - WeiXu
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Meiqi Xing
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Haiju Wei
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Wang Li
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Zhengwei Li
- Fisheries Technology Extension Station of Heilongjiang Province, Daqing 166299, China
| | - Xiaohua Teng
- College of Life Science, Northeast Agricultural University, Harbin 150036, China.
| | - Longwu Geng
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
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Lynch EB, Kapur N, Goretsky T, Bradford EM, Vekaria H, Bhogoju S, Hassan SA, Pauw E, Avdiushko MG, Lee G, Gao T, Sullivan PG, Barrett TA. Phosphatidylinositol 3-Kinase Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00151-8. [PMID: 40316215 DOI: 10.1016/j.ajpath.2025.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/24/2025] [Accepted: 04/10/2025] [Indexed: 05/04/2025]
Abstract
Intestinal stem cell (ISC) signaling maintains the balance of self-renewal and differentiation. The role of phosphatidylinositol 3-kinase (PI3K) signaling in ISC responses to radiation was interrogated using Villin-Cre pik3r1lox/lox (p85ΔIEC) mice and p85α-deficient human enteroids (shp85α). Lethal whole-body irradiation in mice was performed to monitor PI3K-mediated survival responses. Rectal biopsies from patients with radiation proctitis were examined by immunohistochemistry for the PI3K/Akt- and Wnt-target survivin. The intestinal epithelial cells (IECs) from p85ΔIEC mice showed increased protein levels of phosphorylated phosphatase and tensin homolog, phosphorylated AktSer473, survivin, cyclin D1, and ρ-β-cateninSer552, as well as increased mRNA for ISC/progenitor cell. In situ hybridization showed that enhanced PI3K signaling reduced Lgr5+ cells but expansion of Axin2+ cells. The shp85α enteroids showed increased mRNA expression of Wnt targets and transcription factor ASCL2, needed for dedifferentiation-mediated restoration of ablated ISCs. The p85α-deficient enteroids showed reduced HES1 mRNA and increases in secretory (ATOH1/MATH1) signaling determinants GFI1 and SPDEF, indicative of reduced NOTCH signaling. Seahorse analyses and phosphorylated p38 staining in IECΔp85 mice indicated that enhanced PI3K signaling led to increased IEC mitochondrial respiration and reactive oxygen species generation. Expression of survivin correlated with the radiation injury in patients. The current data indicate that PI3K signaling increases mitochondrial reactive oxygen species generation and ISC activation that improves IEC recovery from radiation-induced injury. The results suggest that increasing PI3K signaling and induced mitochondrial respiration may improve mucosal healing from radiation injury in patients.
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Affiliation(s)
- Evan B Lynch
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky; Division of Plastic Surgery, Department of Surgery, University of Kentucky, Lexington, Kentucky; Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Neeraj Kapur
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Tatiana Goretsky
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily M Bradford
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Hemendra Vekaria
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Sarayu Bhogoju
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Syed A Hassan
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily Pauw
- College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Margarita G Avdiushko
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Goo Lee
- The University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, Alabama
| | - Tianyan Gao
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky
| | - Patrick G Sullivan
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Terrence A Barrett
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky.
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48
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Esposto MP, Mahlaoui N, Abolhassani H, Van Aerde K, Cesaro S, Chandra A, Ehl S, Kracker S, Suarez F, Barlogis V, Parisi A, Maccari ME, Chinello M. Case Report: Activated PI3-kinase-δ syndrome and ovarian malignancies: a case series from the European ESID-APDS registry. Front Immunol 2025; 16:1572194. [PMID: 40370432 PMCID: PMC12075536 DOI: 10.3389/fimmu.2025.1572194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/07/2025] [Indexed: 05/16/2025] Open
Abstract
Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.
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Affiliation(s)
- Maria Pia Esposto
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Nizar Mahlaoui
- Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Hassan Abolhassani
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Koen Van Aerde
- Department of pediatric infectious disease and immunology, Amalia Children’s Hospital, Radboudumc, Nijmegen, Netherlands
| | - Simone Cesaro
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Anita Chandra
- Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sven Kracker
- Laboratory of Lymphocyte Activation and Susceptibility to Epstein Barr Virus (EBV) infection, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France
| | - Felipe Suarez
- Université Paris Cité, Inserm U-1163, Institut Imagine, Laboratoire of Hematological Disorders, Paris, France
- Service d’Hématologie Adulte and Centre de référence des déficits immunitaires héréditaires (CEREDIH), AP-HP, Hôpital Necker-Enfants Malades, Paris, France
| | - Vincent Barlogis
- Department of Pediatric Hematology, Immunology and Oncology, APHM, Hôpital de la Timone Enfants, Marseille, France
- CEReSS Research Unit EA 3279 and Department of Public Health, Aix Marseille University, School of Medicine, Marseille, France
- Aix Marseille University, School of Medicine, Marseille, France
| | - Alice Parisi
- Department of Pathological Anatomy, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Maria Elena Maccari
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children’s Hospital, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Matteo Chinello
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
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49
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Ge H, Guo N, Liu Y, Lang B, Yin X, Yu X, Zhang Z, Fu Y, Ding H, Hu Q, Han X, Geng W, Shang H, Jiang Y. The inhibitory receptor LAG3 affects NK cell IFN-γ production through glycolysis and the PSAT1/STAT1/IFNG pathway. mBio 2025:e0023025. [PMID: 40298450 DOI: 10.1128/mbio.00230-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 02/26/2025] [Indexed: 04/30/2025] Open
Abstract
Natural killer (NK) cells are integral to the innate immune system and crucial for antiviral defense. NK cell activation and functional state are suppressed by inhibitory receptors. Lymphocyte activation gene 3 (LAG3) is an important inhibitory receptor, but the associated signaling pathways that regulate lymphocyte function remain to be elucidated. In addition, the effect of LAG3 on NK cell function during HIV infection and its specific mechanisms are unclear. In this study, we observed that LAG3 expression by NK cells is elevated in HIV-infected individuals and inversely correlated with CD4/CD8 ratio and CD4+ T cell count. LAG3+ NK cells produce lower levels of interferon-gamma (IFN-γ), but LAG3-Fc protein significantly enhances NK cell function. The activation of LAG3 significantly inhibits IFN-γ production and Ki67 expression by NK cells. Our transcriptome sequencing and in vitro data show for the first time that LAG3 not only regulates the transcription of MYC and several glycolysis-related enzyme genes via the PI3K/AKT/mTOR signaling pathway to inhibit glycolysis in NK cells but also suppresses the STAT1/IFNG pathway by upregulating PSAT1 expression, thus limiting IFN-γ production by NK cells via these two different pathways. Overall, these results provide new insights and identify potential targets for immunotherapy of HIV infection. IMPORTANCE We demonstrate that lymphocyte activation gene 3 (LAG3) expression is upregulated on natural killer (NK) cells during HIV infection. LAG3 inhibits glycolysis in NK cells and also upregulates PSAT1 expression to suppress activation of the STAT1/IFNG pathway, thus restricting interferon-gamma production by NK cells. These results provide new clues to study the effects of LAG3 on the metabolism and functional exhaustion of NK cells and offer a potential target for the treatment of HIV.
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Affiliation(s)
- Hongchi Ge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Nan Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yufei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Bin Lang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaowan Yin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaowen Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Zining Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yajing Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Haibo Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Qinghai Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaoxu Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Wenqing Geng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Hong Shang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yongjun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
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50
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Timilsina S, Huang JY, Abdelfattah N, Medina D, Singh D, Abdulsahib S, Subbarayalu P, Do TP, Venkata PP, Nirzhor S, Prochnau J, Bhandari M, Zheng S, Chen Y, Huang G, Mukherjee N, Hromas R, Sung P, Kaklamani V, Vadlamudi R, Zhang N, Rao MK. Epigenetic silencing of DNA sensing pathway by FOXM1 blocks stress ligand-dependent antitumor immunity and immune memory. Nat Commun 2025; 16:3967. [PMID: 40295473 PMCID: PMC12037779 DOI: 10.1038/s41467-025-59186-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 04/14/2025] [Indexed: 04/30/2025] Open
Abstract
The interplay between tumor cells and the microenvironment significantly influences cancer progression. Here, we report a significant role of the transcription factor FOXM1 in shaping the tumor immune landscape. Single-cell sequencing reveals that tumor-intrinsic FOXM1 creates an immune-suppressive tumor microenvironment by inhibiting expression of stress ligands (including ULBP1) on cancer cells, thereby blocking NKG2D-NKG2DL interactions critical for priming natural killer- and T cell-mediated cytotoxicity of cancer cells. FOXM1 suppresses ULBP1 expression by epigenetically silencing the DNA-sensing protein STING using a DNMT1-UHRF1 complex, which in turn inhibits the unfolded protein response protein CHOP from activating ULBP1. Importantly, cancer patients with higher levels of FOXM1 and DNMT1, and lower levels of STING and ULBP1, have worse survival and are less responsive to immunotherapy. Collectively, our findings provide key insight into how a tumor-intrinsic transcription factor epigenetically shapes the tumor immune microenvironment, with strong implications for refining existing and designing new cancer immunotherapies.
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Affiliation(s)
| | - Jian Yu Huang
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
| | - Nourhan Abdelfattah
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA
| | - Daisy Medina
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Deepika Singh
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Shahad Abdulsahib
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Panneerdoss Subbarayalu
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Trong Phat Do
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Prabhakar Pitta Venkata
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Saif Nirzhor
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Jack Prochnau
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
| | - Mukund Bhandari
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Siyuan Zheng
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Yidong Chen
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Gang Huang
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | | | - Robert Hromas
- Department of Medicine, UT Health, San Antonio, TX, USA
| | - Patrick Sung
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Biochemistry & Structural Biology, UT Health San Antonio, San Antonio, TX, USA
| | | | - Ratna Vadlamudi
- Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, USA
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Nu Zhang
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA
- Department of Microbiology, Immunology & Molecular Genetics, UT Health, San Antonio, TX, USA
| | - Manjeet K Rao
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA.
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA.
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