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Tatsumi Y, Masuda T, Watanabe T, Utomo RY, Zulfin UM, Meiyanto E, Ozaki T, Suenaga Y, Kamikubo Y. Antitumor effect of curcumin analog on osteosarcoma through the inhibition of p300‑mediated histone acetylation. Oncol Rep 2025; 53:47. [PMID: 39981920 DOI: 10.3892/or.2025.8880] [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: 10/11/2024] [Accepted: 01/29/2025] [Indexed: 02/22/2025] Open
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Histone acetyltransferases (HATs), such as p300, CBP and PCAF, modulate numerous biological processes, including cellular proliferation and oncogenesis, through histone acetylation. In the present study, it was investigated whether the curcumin analogs such as pentagamavunon‑1 (PGV‑1) and chemoprevention curcumin analog‑1.1 (CCA‑1.1) could target p300 and suppress OS. Computational analysis indicated that PGV‑1 and CCA‑1.1 bind to the HAT domain of p300. Accordingly, these analogs efficiently inhibited the HAT activity of p300 in vitro and promoted OS cell apoptosis, accompanied by downregulation of acetylated histone H3 at Lys‑27 and phosphorylated oncogenic STAT3 at Tyr‑705. Finally, it was found that PGV‑1 and CCA‑1.1 but not PGV‑1, significantly attenuates the growth of OS developed on the chicken egg chorioallantoic membrane (CAM). Collectively, the present results strongly suggest that curcumin analog‑mediated targeting of p300 might provide a clue to develop an effective treatment strategy against patients with OS.
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Affiliation(s)
- Yasutoshi Tatsumi
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Tatsuya Masuda
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Takayoshi Watanabe
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Rohmad Yudi Utomo
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Ummi Maryam Zulfin
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Edy Meiyanto
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Toshinori Ozaki
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Yusuke Suenaga
- Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Yasuhiko Kamikubo
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
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Zhou H, Zhang R, Men K, Tang L, Wang Y, Yang L. A Novel Systemic siDR6 Delivery System Based on DP7-C for the Treatment of Metastatic Lung Cancer. Int J Nanomedicine 2025; 20:3623-3642. [PMID: 40125426 PMCID: PMC11930241 DOI: 10.2147/ijn.s488213] [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: 09/01/2024] [Accepted: 03/06/2025] [Indexed: 03/25/2025] Open
Abstract
Background The treatment of metastatic lung cancer, a common complication of many primary cancers, has historically been a significant clinical challenge. Once lung metastasis occurs, patients' survival is often significantly shortened. Therefore, prevention and treatment of lung metastases is an important aspect of cancer treatment. In this study, a simple, low-toxicity, cholesterol-modified cationic cell-penetrating peptide DP7 (DP7-C), in combination with siDR6 was used for intravenous administration for the treatment of lung metastases. Methods Initially, clinical databases were analyzed to determine the expression levels of death receptor 6 (DR6) in metastatic tumors and the correlation between DR6 expression and patient survival times. The DP7-C/siDR6 micelles were prepared by a self-assembly method. By cultivating 293T, B16F10 and LL2 cells, the in vitro experiments were performed to assess the transfection efficiency, safety and anti-cancer ability of DP7-C/siDR6, while its targeting efficiency and prevention of lungs were investigated by mouse experiments. Furthermore, the therapeutic efficacy of DP7-C/siDR6 was demonstrated in the LL2 model of lung cancer in situ, the B16F10 model of artificial lung metastasis, and the 4T1 model of spontaneous lung metastasis. Results The clinical data analysis revealed that DR6 was highly expressed in the majority of metastatic tumors and that patients with high DR6 expression exhibited significantly shorter survival times. The DP7-C/siDR6 showed high transfection efficiency, and it could inhibit tumor cell growth by suppressing the STAT3 signaling pathway. Subsequent mouse experiments demonstrated that intravenous administration of DP7-C/siDR6 resulted in efficient lung targeting. The inhibition of DR6 expression on lung endothelial cells was found to prevent metastasis-induced primary necrosis of lung endothelial cells, thereby preventing tumor metastasis. And the DP7-C/siDR6 treatment showed excellent therapeutic efficacy in the tumor models. Conclusion The systemic delivery of DP7-C micelles carrying siDR6 provide an alternative therapeutic strategy to halt cancer lung metastasis.
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Affiliation(s)
- Hongyou Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Rui Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Ke Men
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Lin Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Yusi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
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Lyu WY, Cao J, Deng WQ, Huang MY, Guo H, Li T, Lin LG, Lu JJ. Xerophenone H, a naturally-derived proteasome inhibitor, triggers apoptosis and paraptosis in lung cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156647. [PMID: 40112632 DOI: 10.1016/j.phymed.2025.156647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 03/03/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Polycyclic polyprenylated acylphloroglucinols (PPAPs) characterized by unique chemical architectures, exhibit diverse pharmacological activities. Xerophenone H (XeH) is a PPAP extracted from the plant Garcinia multiflora Champ. ex Benth. (Clusiaceae) with a novel and unique chemical structure. Although in vitro screening has revealed the anti-cancer activity of XeH, whose in vivo effectiveness and mechanistic basis required systematic investigation. METHODS Cytotoxic effects were evaluated through MTT and colony formation assays. A subcutaneous xenograft model was established to assess in vivo anti-cancer efficacy. To elucidate the underlying mechanism of the anti-cancer effect of XeH, RNA-sequencing and western blotting were performed. A proteasome activity assay was conducted to quantify the effect of XeH. Molecular docking and cellular thermal shift assays were conducted to identify the potential molecular target for XeH. RESULTS XeH demonstrated concentration-dependent cytotoxicity in A549 cells (IC₅₀ = 12.16 μM at 48 h). Intratumoral administration (10 mg/kg triweekly) achieved 38.6 % tumor growth inhibition. XeH simultaneously triggered apoptosis and paraptosis in A549 and H460 cells. Mechanistically, XeH promoted the formation of protein aggregates and induced significant endoplasmic reticulum stress in lung cancer cells by directly interacting with PSMB5 and inhibiting proteasome activity. CONCLUSIONS XeH, a novel PPAP, was identified as a novel proteasome inhibitor. It effectively downregulated proteasome activity, and induced both apoptosis and paraptosis in lung cancer cells.
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Affiliation(s)
- Wen-Yu Lyu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Jun Cao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Wei-Qing Deng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Mu-Yang Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Hongwei Guo
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, Nanning, 530021, China
| | - Ting Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao SAR, 999078, China.
| | - Li-Gen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, 999078, China.
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao SAR, 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, 999078, China.
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Li L, Zhou H, Li M, Liu W, Li Y, Xu H, Jiang J, Yang Y, Gong Y. Salvianolic acid B ameliorates hepatic fibrosis via inhibiting p300/CBP. Eur J Pharmacol 2025; 998:177495. [PMID: 40058756 DOI: 10.1016/j.ejphar.2025.177495] [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: 08/06/2024] [Revised: 11/23/2024] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
Salvianolic acid B (Sal B), an active ingredient extracted from Salvia miltiorrhiza Bunge, has shown hepatic anti-fibrotic activity. Hepatic stellate cells (HSCs) activation is considered the determining event in liver fibrogenesis. E1A binding protein p300 (p300)/CREB binding protein (CBP) is an attractive target for inhibiting HSCs activation. But whether Sal B inhibits hepatic fibrosis through suppressing p300/CBP is unknown. We used DEN/CCl4/C2H5OH to establish a mouse model of hepatic fibrosis and detect the effects of Sal B on liver function, pathological alterations, and p300/CBP expression. TGF-β1 was used to induce LX-2 cells for in vitro experimental validation. Additionally, the effects of Sal B on LX-2 activation were explored using the p300/CBP activator CTB, and molecular docking was used to predict the interaction between Sal B and p300. The in vivo results demonstrated that Sal B improved liver function, reversed pathological changes, reduced collagen synthesis, and downregulated the protein levels of p300 and CBP in DEN/CCl4/C2H5OH-induced hepatic fibrosis mice. The in vitro results showed that Sal B inhibited LX-2 cells activation and decreased both the mRNA and protein levels of p300 and CBP. Furthermore, the p300/CBP activator CTB reversed the inhibitory effect of Sal B on LX-2 cells activation. Molecular docking showed that Sal B bound well to p300 with a high degree of match and a binding energy of -14.859 kcal/mol. Our study revealed that Sal B ameliorates hepatic fibrosis, which likely via inhibition of p300/CBP. However, the specific binding site deserves further exploration.
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Affiliation(s)
- Lili Li
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Huabiao Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Miaomiao Li
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Wenbo Liu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Yuxuan Li
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Hanyang Xu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China
| | - Jiemei Jiang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Yan Yang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China.
| | - Yongfang Gong
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei, 230032, China; School of Nursing, Anhui Medical University, Hefei, 230032, China.
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Sui Y, Shen Z, Wang Z, Feng J, Zhou G. Lactylation in cancer: metabolic mechanism and therapeutic strategies. Cell Death Discov 2025; 11:68. [PMID: 39979245 PMCID: PMC11842571 DOI: 10.1038/s41420-025-02349-4] [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: 12/11/2024] [Revised: 01/23/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
Recent progress in cancer metabolism research has identified lactylation as a critical post-translational modification influencing tumor development and progression. The process relies on lactate accumulation and the activation of lactate-sensitive acyltransferases. Beyond its role in epigenetic regulation, lactylation has emerged as a significant factor in tumor metabolism and evolution, offering fresh opportunities for developing targeted therapies that transcend traditional approaches. This review explores the growing importance of lactylation in cancer biology and highlights its potential for advancing diagnostic tools and therapeutic strategies.
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Affiliation(s)
- Ying Sui
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Ziyang Shen
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Zhenling Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jifeng Feng
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China.
| | - Guoren Zhou
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China.
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Wang W, Wang H, Wang Q, Yu X, Ouyang L. Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies. Front Immunol 2025; 15:1513047. [PMID: 39867891 PMCID: PMC11757118 DOI: 10.3389/fimmu.2024.1513047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 12/27/2024] [Indexed: 01/28/2025] Open
Abstract
Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context of yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely as the terminal product of glycolysis but also as a nexus for initiating physiological and pathological responses within the body. Lysine lactylation (Kla), a novel post-translational modification (PTM) of proteins, has emerged as a pivotal mechanism by which lactate exerts its regulatory influence. This epigenetic modification has the potential to alter gene expression patterns, thereby impacting physiological and pathological processes. Increasing evidence indicates a correlation between lactylation and adverse prognosis in various malignancies. Consequently, this review article aims to encapsulate the proteins that interact with lactate, elucidate the role of lactylation in tumorigenesis and progression, and explore the potential therapeutic targets afforded by the modulation of lactylation. The objective of this review is to clarify the oncogenic significance of lactylation and to provide a strategic framework for future research directions in this burgeoning field.
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Affiliation(s)
- Wenjuan Wang
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Hong Wang
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Qi Wang
- Co-Innovation Center for Sustainable Forestry in Southern China, College of Life Sciences, Nanjing Forestry University, Nanjing, China
| | - Xiaojing Yu
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Liangliang Ouyang
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
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Gronkowska K, Robaszkiewicz A. Genetic dysregulation of EP300 in cancers in light of cancer epigenome control - targeting of p300-proficient and -deficient cancers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200871. [PMID: 39351073 PMCID: PMC11440307 DOI: 10.1016/j.omton.2024.200871] [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: 10/04/2024]
Abstract
Some cancer types including bladder, cervical, and uterine cancers are characterized by frequent mutations in EP300 that encode histone acetyltransferase p300. This enzyme can act both as a tumor suppressor and oncogene. In this review, we describe the role of p300 in cancer initiation and progression regarding EP300 aberrations that have been identified in TGCA Pan-Cancer Atlas studies and we also discuss possible anticancer strategies that target EP300 mutated cancers. Copy number alterations, truncating mutations, and abnormal EP300 transcriptions that affect p300 abundance and activity are associated with several pathological features such as tumor grading, metastases, and patient survival. Elevated EP300 correlates with a higher mRNA level of other epigenetic factors and chromatin remodeling enzymes that co-operate with p300 in creating permissive conditions for malignant transformation, tumor growth and metastases. The status of EP300 expression can be considered as a prognostic marker for anticancer immunotherapy efficacy, as EP300 mutations are followed by an increased expression of PDL-1.HAT activators such as CTB or YF2 can be applied for p300-deficient patients, whereas the natural and synthetic inhibitors of p300 activity, as well as dual HAT/bromodomain inhibitors and the PROTAC degradation of p300, may serve as strategies in the fight against p300-fueled cancers.
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Affiliation(s)
- Karolina Gronkowska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
- Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Agnieszka Robaszkiewicz
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
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Feng T, Zhang H, Zhou Y, Zhu Y, Shi S, Li K, Lin P, Chen J. Roles of posttranslational modifications in lipid metabolism and cancer progression. Biomark Res 2024; 12:141. [PMID: 39551780 PMCID: PMC11571667 DOI: 10.1186/s40364-024-00681-y] [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: 07/10/2024] [Accepted: 10/30/2024] [Indexed: 11/19/2024] Open
Abstract
Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.
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Affiliation(s)
- Tianyu Feng
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
| | - He Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
| | - Yanjie Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
| | - Yalan Zhu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
| | - Shiya Shi
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China
| | - Kai Li
- Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China.
| | - Ping Lin
- Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China.
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China.
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, Sichuan Province, 610041, China.
- Clinical Laboratory Medicine Research Center of West China Hospital, #37, Guo Xue Lane, Chengdu, Sichuan Province, 610041, China.
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Patwa N, Chauhan R, Chauhan A, Kumar M, Ramniwas S, Mathkor DM, Saini AK, Tuli HS, Haque S, Slama P. Garcinol in gastrointestinal cancer prevention: recent advances and future prospects. J Cancer Res Clin Oncol 2024; 150:370. [PMID: 39066940 PMCID: PMC11283395 DOI: 10.1007/s00432-024-05880-6] [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: 05/05/2024] [Accepted: 07/03/2024] [Indexed: 07/30/2024]
Abstract
Gastrointestinal cancers continue to pose a significant global health challenge, with millions of new cases diagnosed each year. Despite advancements in treatment, the prognosis for many patients remains poor. This article explores the potential of garcinol, a polyisoprenylated benzophenone found in various Garcinia species, as a therapeutic agent against gastrointestinal malignancies. The objective is to review recent research on garcinol's anticancer properties, its mechanisms of action, and safety aspects. Garcinol exhibits anticancer effects in esophageal, gastric, colorectal, pancreatic, and liver cancers by inhibiting metastasis, inducing apoptosis, and targeting key molecular pathways in cancer progression. Nanotechnology is explored as a means to enhance garcinol delivery and efficacy. Safety assessments suggest a promising toxicity profile. Garcinol shows significant potential as a natural therapeutic agent for gastrointestinal cancers, and future research is needed on optimizing its delivery, exploring synergistic combinations, and conducting clinical trials to validate its efficacy and safety for clinical applications.
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Affiliation(s)
- Nitika Patwa
- Department of Chemistry, Indian Institute of Technology, Delhi, India
| | - Ritu Chauhan
- Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, 248002, India
| | - Abhishek Chauhan
- Amity Institute of Environmental Toxicology Safety and Management, Amity University, Noida, U.P, India
| | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur-Ambala, 134007, Haryana, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, 140413, India
| | - Darin Mansor Mathkor
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia
| | - Adesh Kumar Saini
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), 133207, Mullana, Ambala, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), 133207, Mullana, Ambala, India
| | - Shafiul Haque
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, 11022801, Lebanon.
| | - Petr Slama
- Laboratory of Animal Immunology and Biotechnology, Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, 61300, Brno, Czech Republic.
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Xiao X, Luo S, Huang J, Wan B, Bi N, Wang J. Synergistic effects of Ω-3 polyunsaturated fatty acid supplementation and programmed cell death protein 1 blockade on tumor growth and immune modulation in a xenograft model of esophageal cancer. Clin Nutr ESPEN 2024; 61:308-315. [PMID: 38777449 DOI: 10.1016/j.clnesp.2024.03.036] [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: 11/01/2023] [Revised: 02/16/2024] [Accepted: 03/29/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), remains a significant global health challenge with limited survival rates. This study aimed to elucidate the combined effects of immune-modulating nutrition (IMN) with Ω-3 polyunsaturated fatty acid (PUFA) supplementation and anti-programmed cell death protein 1 (PD-1) treatment on tumor growth and immune responses in a xenograft model of ESCC. METHODS A total of 36 C57BL/6 mice were used to construct a xenograft model using the mouse esophageal cancer cell line AKR. Mice were subjected to treatment with anti- PD-1 antibody combined with either Ω-3 PUFA-rich or Ω-3 PUFA-deficient nutrition. Tumor growth, immune markers, cytokine profiles, and metabolic changes were evaluated. RESULTS The combination of anti-PD-1 and Ω-3 PUFA supplementation significantly inhibited tumor growth more effectively than anti-PD-1 treatment alone. Enhanced expression of immune markers PD-L1 and CD3 was observed in Ω-3 PUFA-fed mice. Additionally, compared with anti-PD-1 therapy and anti-PD-1 plus Ω-3 PUFA-deficient nutrition, Ω-3 PUFAs intensified alterations in key chemokines and cytokines, including elevated IL-12, IFN-γ, and GM-CSF levels, and reduced CXCL12 levels. However, Ω-3 PUFAs did not significantly alter the glycolysis and tryptophan metabolic program induced by anti-PD-1. CONCLUSION Our findings indicated the potential synergetic therapeutic benefits of combining anti-PD-1 treatment with Ω-3 PUFA supplementation in ESCC, which offered promising avenue for further research.
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Affiliation(s)
- Xi Xiao
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China; Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Shihong Luo
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Jianbing Huang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Bao Wan
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Jianyang Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
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11
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Yedla P, Bhamidipati P, Syed R, Amanchy R. Working title: Molecular involvement of p53-MDM2 interactome in gastrointestinal cancers. Cell Biochem Funct 2024; 42:e4075. [PMID: 38924101 DOI: 10.1002/cbf.4075] [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: 02/16/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024]
Abstract
The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53-MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio-temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53-mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53-MDM2 complex for ubiquitin-mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53-MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co-localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53-MDM2 interactome. p53-MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53-MDM2 interactors and the effectors that form an epicenter for the development of next-generation molecules for understanding and targeting GI cancers.
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Affiliation(s)
- Poornachandra Yedla
- Division of Applied Biology, CSIR-IICT (Indian Institute of Chemical Technology), Ministry of Science and Technology (GOI), Hyderabad, Telangana, India
- Department of Pharmacogenomics, Institute of Translational Research, Asian Healthcare Foundation, Hyderabad, Telangana, India
| | - Pranav Bhamidipati
- Division of Applied Biology, CSIR-IICT (Indian Institute of Chemical Technology), Ministry of Science and Technology (GOI), Hyderabad, Telangana, India
- Department of Life Sciences, Imperial College London, London, UK
| | - Riyaz Syed
- Division of Applied Biology, CSIR-IICT (Indian Institute of Chemical Technology), Ministry of Science and Technology (GOI), Hyderabad, Telangana, India
| | - Ramars Amanchy
- Division of Applied Biology, CSIR-IICT (Indian Institute of Chemical Technology), Ministry of Science and Technology (GOI), Hyderabad, Telangana, India
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12
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Li X, Xiong H, Mou X, Huang C, Thomas ER, Yu W, Jiang Y, Chen Y. Androgen receptor cofactors: A potential role in understanding prostate cancer. Biomed Pharmacother 2024; 173:116338. [PMID: 38417290 DOI: 10.1016/j.biopha.2024.116338] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 03/01/2024] Open
Abstract
Prostate cancer (PCa) is witnessing a concerning rise in incidence annually, with the androgen receptor (AR) emerging as a pivotal contributor to its growth and progression. Mounting evidence underscores the AR's ability to recruit cofactors, influencing downstream gene transcription and thereby fueling the proliferation and metastasis of PCa cells. Although, clinical strategies involving AR antagonists provide some relief, managing castration resistant prostate cancer (CRPC) remains a formidable challenge. Thus, the need of the hour lies in unearthing new drugs or therapeutic targets to effectively combat PCa. This review encapsulates the pivotal roles played by coactivators and corepressors of AR, notably androgen receptor-associated protein (ARA) and steroid receptor Coactivators (SRC) in PCa. Our data unveils how these cofactors intricately modulate histone modifications, cell cycling, SUMOylation, and apoptosis through their interactions with AR. Among the array of cofactors scrutinised, such as ARA70β, ARA24, ARA160, ARA55, ARA54, PIAS1, PIAS3, SRC1, SRC2, SRC3, PCAF, p300/CBP, MED1, and CARM1, several exhibit upregulation in PCa. Conversely, other cofactors like ARA70α, PIASy, and NCoR/SMRT demonstrate downregulation. This duality underscores the complexity of AR cofactor dynamics in PCa. Based on our findings, we propose that manipulating cofactor regulation to modulate AR function holds promise as a novel therapeutic avenue against advanced PCa. This paradigm shift offers renewed hope in the quest for effective treatments in the face of CRPC's formidable challenges.
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Affiliation(s)
- Xiang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Haojun Xiong
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xingzhu Mou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Cancan Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | | | - Wenjing Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Yu Jiang
- The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
| | - Yan Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
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13
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Jiang WM, Tian JY, Guo YH, Qiu LH, Luo XY, Huang YY, Long H, Zhang LJ, Lin P, Xu XX, Wu LL, Ma GW. The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up. Cancer Cell Int 2024; 24:119. [PMID: 38553712 PMCID: PMC10981364 DOI: 10.1186/s12935-024-03286-5] [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: 10/26/2023] [Accepted: 02/29/2024] [Indexed: 04/01/2024] Open
Abstract
OBJECTIVE This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.
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Affiliation(s)
- Wen-Mei Jiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Jia-Yuan Tian
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Yi-Han Guo
- Department of Scientific Research, Shaanxi Academy of Social Sciences, Xi'an, 710065, China
| | - Li-Hong Qiu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Xing-Yu Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Yang-Yu Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Hao Long
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Lan-Jun Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Peng Lin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China
| | - Xin-Xin Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China.
- Central Hospital of Minhang District, Shanghai, 201100, P. R. China.
| | - Lei-Lei Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China.
- Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
| | - Guo-Wei Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, P. R. China.
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14
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Khan A, Khan A, Khan MA, Malik Z, Massey S, Parveen R, Mustafa S, Shamsi A, Husain SA. Phytocompounds targeting epigenetic modulations: an assessment in cancer. Front Pharmacol 2024; 14:1273993. [PMID: 38596245 PMCID: PMC11002180 DOI: 10.3389/fphar.2023.1273993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/09/2023] [Indexed: 04/11/2024] Open
Abstract
For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.
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Affiliation(s)
- Aqsa Khan
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Asifa Khan
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Mohammad Aasif Khan
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
- Department of Radiation Oncology, The University of Texas Health Science Centre at San Antonio, San Antonio, TX, United States
| | - Zoya Malik
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Sheersh Massey
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Rabea Parveen
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Saad Mustafa
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Anas Shamsi
- Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Syed A. Husain
- Department of Bioscience, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
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15
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GE WEN, LI YA, RUAN YUTING, WU NINGXIA, MA PEI, XU TONGPENG, SHU YONGQIAN, WANG YINGWEI, QIU WEN, ZHAO CHENHUI. IL-17 induces NSCLC cell migration and invasion by elevating MMP19 gene transcription and expression through the interaction of p300-dependent STAT3-K631 acetylation and its Y705-phosphorylation. Oncol Res 2024; 32:625-641. [PMID: 38560562 PMCID: PMC10972722 DOI: 10.32604/or.2023.031053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/17/2023] [Indexed: 04/04/2024] Open
Abstract
The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer (NSCLC). Although researchers have disclosed that interleukin 17 (IL-17) can increase matrix metalloproteinases (MMPs) induction causing NSCLC cell metastasis, the underlying mechanism remains unclear. In the study, we found that IL-17 receptor A (IL-17RA), p300, p-STAT3, Ack-STAT3, and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17. p300, STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3, Ack-STAT3 and MMP19 level as well as the cell migration and invasion. Mechanism investigation revealed that STAT3 and p300 bound to the same region (-544 to -389 nt) of MMP19 promoter, and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity, p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17. Meanwhile, p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact, synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion. Besides, the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300, STAT3 or MMP19 gene plus IL-17 treatment, the nodule number, and MMP19, Ack-STAT3, or p-STAT3 production in the lung metastatic nodules were all alleviated. Collectively, these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation, which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
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Affiliation(s)
- WEN GE
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - YA LI
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - YUTING RUAN
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - NINGXIA WU
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - PEI MA
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China
| | - TONGPENG XU
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China
| | - YONGQIAN SHU
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China
| | - YINGWEI WANG
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - WEN QIU
- Department of Immunology, Nanjing Medical University, Nanjing, 210000, China
- Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, 210000, China
| | - CHENHUI ZHAO
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China
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16
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Ding Y, Zhou G, Hu W. Epigenetic regulation of TGF-β pathway and its role in radiation response. Int J Radiat Biol 2024; 100:834-848. [PMID: 38506660 DOI: 10.1080/09553002.2024.2327395] [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: 09/06/2023] [Accepted: 02/27/2024] [Indexed: 03/21/2024]
Abstract
PURPOSE Transforming growth factor (TGF-β) plays a dual role in tumor progression as well as a pivotal role in radiation response. TGF-β-related epigenetic regulations, including DNA methylation, histone modifications (including methylation, acetylation, phosphorylation, ubiquitination), chromatin remodeling and non-coding RNA regulation, have been found to affect the occurrence and development of tumors as well as their radiation response in multiple dimensions. Due to the significance of radiotherapy in tumor treatment and the essential roles of TGF-β signaling in radiation response, it is important to better understand the role of epigenetic regulation mechanisms mediated by TGF-β signaling pathways in radiation-induced targeted and non-targeted effects. CONCLUSIONS By revealing the epigenetic mechanism related to TGF-β-mediated radiation response, summarizing the existing relevant adjuvant strategies for radiotherapy based on TGF-β signaling, and discovering potential therapeutic targets, we hope to provide a new perspective for improving clinical treatment.
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Affiliation(s)
- Yunan Ding
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Guangming Zhou
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Wentao Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
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17
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Zou J, Chen H, Fan X, Qiu Z, Zhang J, Sun J. Garcinol prevents oxidative stress-induced bone loss and dysfunction of BMSCs through NRF2-antioxidant signaling. Cell Death Discov 2024; 10:82. [PMID: 38365768 PMCID: PMC10873372 DOI: 10.1038/s41420-024-01855-1] [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: 07/21/2023] [Revised: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/18/2024] Open
Abstract
There are multiple published data showing that excessive oxidative stress contributes to bone loss and even bone tissue damage, and it is also correlated with the pathophysiology of bone degenerative diseases, including osteoporosis (OP). Garcinol, a polyisoprenylated benzophenone derivative, has been recently established as an anti-oxidant agent. However, it remains elusive whether Garcinol protects bone marrow mesenchymal stem cells (BMSCs) and bone tissue from oxidative stress-induced damage. Here, we explored the potential effects of Garcinol supplementation in ameliorating oxidative stimulation-induced dysfunction of BMSCs and bone loss in osteoporotic mice. In this study, we verified that Garcinol exerted potent protective functions in the hydrogen peroxide (H2O2)-induced excessive oxidative stress and dysfunction of BMSCs. Besides, Garcinol was also identified to improve the reduced bone mass and abnormal lineage commitment of BMSCs in the condition of OP by suppressing the oxidative stimulation. Subsequent analysis revealed that nuclear factor erythroid 2-related factor 2 (NRF2) might be a key regulator in the sheltering effects of Garcinol on the H2O2-regulated oxidative stress, and the protective functions of Garcinol was mediated by NRF2-antioxidant signaling. Collectively, Garcinol prevented oxidative stress-related BMSC damage and bone loss through the NRF2-antioxidant signaling, which suggested the promising therapeutic values of Garcinol in the treatment of oxidative stress-related bone loss. Therefore, Garcinol might contribute to treating OP.
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Affiliation(s)
- Jilong Zou
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongjun Chen
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinming Fan
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhenrui Qiu
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiale Zhang
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiabing Sun
- Department of Orthopaedics, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
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18
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Rizvi SMD, Almazni IA, Moawadh MS, Alharbi ZM, Helmi N, Alqahtani LS, Hussain T, Alafnan A, Moin A, Elkhalifa AO, Awadelkareem AM, Khalid M, Tiwari RK. Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches. Front Chem 2024; 12:1352009. [PMID: 38435669 PMCID: PMC10904546 DOI: 10.3389/fchem.2024.1352009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
Glioblastoma multiforme (GBM) is regarded as the most aggressive form of brain tumor delineated by high cellular heterogeneity; it is resistant to conventional therapeutic regimens. In this study, the anti-cancer potential of garcinol, a naturally derived benzophenone, was assessed against GBM. During the analysis, we observed a reduction in the viability of rat glioblastoma C6 cells at a concentration of 30 µM of the extract (p < 0.001). Exposure to garcinol also induced nuclear fragmentation and condensation, as evidenced by DAPI-stained photomicrographs of C6 cells. The dissipation of mitochondrial membrane potential in a dose-dependent fashion was linked to the activation of caspases. Furthermore, it was observed that garcinol mediated the inhibition of NF-κB (p < 0.001) and decreased the expression of genes associated with cell survival (Bcl-XL, Bcl-2, and survivin) and proliferation (cyclin D1). Moreover, garcinol showed interaction with NF-κB through some important amino acid residues, such as Pro275, Trp258, Glu225, and Gly259 during molecular docking analysis. Comparative analysis with positive control (temozolomide) was also performed. We found that garcinol induced apoptotic cell death via inhibiting NF-κB activity in C6 cells, thus implicating it as a plausible therapeutic agent for GBM.
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Affiliation(s)
- Syed Mohd Danish Rizvi
- Department of Pharmaceutics, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia
| | - Ibrahim A. Almazni
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia
| | - Mamdoh S. Moawadh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Zeyad M. Alharbi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Nawal Helmi
- Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Leena S. Alqahtani
- Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Talib Hussain
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia
| | - Ahmed Alafnan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia
| | - Afrasim Moin
- Department of Pharmaceutics, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia
| | - AbdElmoneim O. Elkhalifa
- Department of Clinical Nutrition, College of Applied Medical Sciences, University of Hail, Ha’il, Saudi Arabia
| | - Amir Mahgoub Awadelkareem
- Department of Clinical Nutrition, College of Applied Medical Sciences, University of Hail, Ha’il, Saudi Arabia
| | - Mohammad Khalid
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Gautam Budh Nagar, India
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19
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Shi H, Cui W, Qin Y, Chen L, Yu T, Lv J. A glimpse into novel acylations and their emerging role in regulating cancer metastasis. Cell Mol Life Sci 2024; 81:76. [PMID: 38315203 PMCID: PMC10844364 DOI: 10.1007/s00018-023-05104-z] [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: 08/30/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 02/07/2024]
Abstract
Metastatic cancer is a major cause of cancer-related mortality; however, the complex regulation process remains to be further elucidated. A large amount of preliminary investigations focus on the role of epigenetic mechanisms in cancer metastasis. Notably, the posttranslational modifications were found to be critically involved in malignancy, thus attracting considerable attention. Beyond acetylation, novel forms of acylation have been recently identified following advances in mass spectrometry, proteomics technologies, and bioinformatics, such as propionylation, butyrylation, malonylation, succinylation, crotonylation, 2-hydroxyisobutyrylation, lactylation, among others. These novel acylations play pivotal roles in regulating different aspects of energy mechanism and mediating signal transduction by covalently modifying histone or nonhistone proteins. Furthermore, these acylations and their modifying enzymes show promise regarding the diagnosis and treatment of tumors, especially tumor metastasis. Here, we comprehensively review the identification and characterization of 11 novel acylations, and the corresponding modifying enzymes, highlighting their significance for tumor metastasis. We also focus on their potential application as clinical therapeutic targets and diagnostic predictors, discussing the current obstacles and future research prospects.
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Affiliation(s)
- Huifang Shi
- Clinical Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, No. 126 Taian Road, Rizhao, 276826, Shandong, China
| | - Weigang Cui
- Central Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, No. 126 Taian Road, Rizhao, 276826, Shandong, China
| | - Yan Qin
- Clinical Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, No. 126 Taian Road, Rizhao, 276826, Shandong, China
| | - Lei Chen
- Clinical Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, No. 126 Taian Road, Rizhao, 276826, Shandong, China
| | - Tao Yu
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China.
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China.
| | - Jie Lv
- Clinical Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, No. 126 Taian Road, Rizhao, 276826, Shandong, China.
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20
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Ahuja P, Yadav R, Goyal S, Yadav C, Ranga S, Kadian L. Targeting epigenetic deregulations for the management of esophageal carcinoma: recent advances and emerging approaches. Cell Biol Toxicol 2023; 39:2437-2465. [PMID: 37338772 DOI: 10.1007/s10565-023-09818-5] [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: 03/16/2023] [Accepted: 06/08/2023] [Indexed: 06/21/2023]
Abstract
Ranking from seventh in incidence to sixth in mortality, esophageal carcinoma is considered a severe malignancy of food pipe. Later-stage diagnosis, drug resistance, and a high mortality rate contribute to its lethality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two main histological subtypes of esophageal carcinoma, with squamous cell carcinoma alone accounting for more than eighty percent of its cases. While genetic anomalies are well known in esophageal cancer, accountability of epigenetic deregulations is also being explored for the recent two decades. DNA methylation, histone modifications, and functional non-coding RNAs are the crucial epigenetic players involved in the modulation of different malignancies, including esophageal carcinoma. Targeting these epigenetic aberrations will provide new insights into the development of biomarker tools for risk stratification, early diagnosis, and effective therapeutic intervention. This review discusses different epigenetic alterations, emphasizing the most significant developments in esophageal cancer epigenetics and their potential implication for the detection, prognosis, and treatment of esophageal carcinoma. Further, the preclinical and clinical status of various epigenetic drugs has also been reviewed.
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Affiliation(s)
- Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India.
| | - Sandeep Goyal
- Department of Internal Medicine, Pt. B.D, Sharma University of Health Sciences, (Haryana), Rohtak, 124001, India
| | - Chetna Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Lokesh Kadian
- Department of Dermatology, School of Medicine, Indiana University, Indianapolis, Indiana, 46202, USA
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21
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Zhang D, Zhang J, Wang Y, Wang G, Tang P, Liu Y, Zhang Y, Ouyang L. Targeting epigenetic modifications in Parkinson's disease therapy. Med Res Rev 2023; 43:1748-1777. [PMID: 37119043 DOI: 10.1002/med.21962] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 01/10/2023] [Accepted: 04/12/2023] [Indexed: 04/30/2023]
Abstract
Parkinson's disease (PD) is a multifactorial disease due to a complex interplay between genetic and epigenetic factors. Recent efforts shed new light on the epigenetic mechanisms involved in regulating pathways related to the development of PD, including DNA methylation, posttranslational modifications of histones, and the presence of microRNA (miRNA or miR). Epigenetic regulators are potential therapeutic targets for neurodegenerative disorders. In the review, we aim to summarize mechanisms of epigenetic regulation in PD, and describe how the DNA methyltransferases, histone deacetylases, and histone acetyltransferases that mediate the key processes of PD are attractive therapeutic targets. We discuss the use of inhibitors and/or activators of these regulators in PD models or patients, and how these small molecule epigenetic modulators elicit neuroprotective effects. Further more, given the importance of miRNAs in PD, their contributions to the underlying mechanisms of PD will be discussed as well, together with miRNA-based therapies.
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Affiliation(s)
- Dan Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Jifa Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yuxi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Guan Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Pan Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yun Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yiwen Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Liang Ouyang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
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22
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Meng M, Tan J, Chen H, Shi Z, Kwan HY, Su T. Brevilin A exerts anti-colorectal cancer effects and potently inhibits STAT3 signaling invitro. Heliyon 2023; 9:e18488. [PMID: 37593607 PMCID: PMC10432182 DOI: 10.1016/j.heliyon.2023.e18488] [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: 12/16/2022] [Revised: 07/05/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related morbidity worldwide, with an estimated of 1.85 million new cases and 850,000 deaths every year. Nevertheless, the current treatment regimens for CRC have many disadvantages, including toxicities and off-targeted side effects. STAT3 (signal transducer and activator of transcription 3) has been considered as a promising molecular target for CRC therapy. Brevilin A, a sesquiterpene lactone compound rich in Centipedae Herba has potent anticancer effects in nasopharyngeal, prostate and breast cancer cells by inhibiting the STAT3 signaling. However, the anti-CRC effect of brevilin A and the underlying mechanism of action have not been fully elucidated. In this study, we aimed to investigate the involvement of STAT3 signaling in the anti-CRC action of brevilin A. Here, HCT-116 and CT26 cell models were used to investigate the anti-CRC effects of brevilin A in vitro. HCT-116 cells overespressing with STAT3 were used to evaluate the involvement of STAT3 signaling in the anti-CRC effect of brevilin A. Screening of 49 phosphorylated tyrosine kinases in the HCT-116 cells after brevilin A treatment was performed by using the human phospho-receptor tyrosine kinase (phospho-RTK) array. Results showed that brevilin A inhibited cell proliferation and cell viability, induced apoptosis, reduced cell migration and invasion, inhibited angiogenesis, lowered the protein expression levels of phospho-Src (Tyr416), phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and inhibited STAT3 activation and nuclear localization. Brevilin A also significantly reduced the protein expression levels of STAT3 target genes, such as MMP-2, VEGF and Bcl-xL. More importantly, over-activation of STAT3 diminished brevilin A's effects on cell viability. All these results suggest that brevilin A exerts potent anti-CRC effects, at least in part, by inhibiting STAT3 signaling. Our findings provide a strong pharmacological basis for the future exploration and development of brevilin A as a novel STAT3-targeting phytotherapeutic agent for CRC treatment.
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Affiliation(s)
- Mingjing Meng
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jincheng Tan
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hui Chen
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhiqiang Shi
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hiu-Yee Kwan
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, China
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23
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Chanda A, Sarkar A, Deng L, Bonni A, Bonni S. Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT-associated phenotypes in mammary organoids. Cell Death Dis 2023; 14:405. [PMID: 37414747 PMCID: PMC10326038 DOI: 10.1038/s41419-023-05921-x] [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: 08/18/2022] [Revised: 06/14/2023] [Accepted: 06/22/2023] [Indexed: 07/08/2023]
Abstract
Protein post-translational modification by the small ubiquitin-like modifier (SUMO) regulates the stability, subcellular localization, and interactions of protein substrates with consequences on cellular responses including epithelial-mesenchymal transition (EMT). Transforming growth factor beta (TGFβ) is a potent inducer of EMT with implications for cancer invasion and metastasis. The transcriptional coregulator SnoN suppresses TGFβ-induced EMT-associated responses in a sumoylation-dependent manner, but the underlying mechanisms have remained largely unknown. Here, we find that sumoylation promotes the interaction of SnoN with the epigenetic regulators histone deacetylase 1 (HDAC1) and histone acetylase p300 in epithelial cells. In gain and loss of function studies, HDAC1 suppresses, whereas p300 promotes, TGFβ-induced morphogenetic changes associated with EMT-related events in three-dimensional multicellular organoids derived from mammary epithelial cells or carcinomas. These findings suggest that sumoylated SnoN acts via the regulation of histone acetylation to modulate EMT-related effects in breast cell organoids. Our study may facilitate the discovery of new biomarkers and therapeutics in breast cancer and other epithelial cell-derived cancers.
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Affiliation(s)
- Ayan Chanda
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Anusi Sarkar
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Lili Deng
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Azad Bonni
- Neuroscience and Rare Diseases, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Shirin Bonni
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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24
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Michalkova R, Mirossay L, Kello M, Mojzisova G, Baloghova J, Podracka A, Mojzis J. Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence. Int J Mol Sci 2023; 24:10354. [PMID: 37373500 DOI: 10.3390/ijms241210354] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/12/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
There is no doubt that significant progress has been made in tumor therapy in the past decades. However, the discovery of new molecules with potential antitumor properties still remains one of the most significant challenges in the field of anticancer therapy. Nature, especially plants, is a rich source of phytochemicals with pleiotropic biological activities. Among a plethora of phytochemicals, chalcones, the bioprecursors of flavonoid and isoflavonoids synthesis in higher plants, have attracted attention due to the broad spectrum of biological activities with potential clinical applications. Regarding the antiproliferative and anticancer effects of chalcones, multiple mechanisms of action including cell cycle arrest, induction of different forms of cell death and modulation of various signaling pathways have been documented. This review summarizes current knowledge related to mechanisms of antiproliferative and anticancer effects of natural chalcones in different types of malignancies including breast cancers, cancers of the gastrointestinal tract, lung cancers, renal and bladder cancers, and melanoma.
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Affiliation(s)
- Radka Michalkova
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Ladislav Mirossay
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Gabriela Mojzisova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Janette Baloghova
- Department of Dermatovenerology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Anna Podracka
- Department of Dermatovenerology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
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25
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Yao W, Guo B, Jin T, Bao Z, Wang T, Wen S, Huang F. Garcinol Promotes the Formation of Slow-Twitch Muscle Fibers by Inhibiting p300-Dependent Acetylation of PGC-1α. Int J Mol Sci 2023; 24:ijms24032702. [PMID: 36769025 PMCID: PMC9916769 DOI: 10.3390/ijms24032702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/31/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
The conversion of skeletal muscle fiber from fast-twitch to slow-twitch is crucial for sustained contractile and stretchable events, energy homeostasis, and anti-fatigue ability. The purpose of our study was to explore the mechanism and effects of garcinol on the regulation of skeletal muscle fiber type transformation. Forty 21-day-old male C57/BL6J mice (n = 10/diet) were fed a control diet or a control diet plus garcinol at 100 mg/kg (Low Gar), 300 mg/kg (Mid Gar), or 500 mg/kg (High Gar) for 12 weeks. The tibialis anterior (TA) and soleus muscles were collected for protein and immunoprecipitation analyses. Dietary garcinol significantly downregulated (p < 0.05) fast myosin heavy chain (MyHC) expression and upregulated (p < 0.05) slow MyHC expression in the TA and soleus muscles. Garcinol significantly increased (p < 0.05) the activity of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and markedly decreased (p < 0.05) the acetylation of PGC-1α. In vitro and in vivo experiments showed that garcinol decreased (p < 0.05) lactate dehydrogenase activity and increased (p < 0.05) the activities of malate dehydrogenase and succinic dehydrogenase. In addition, the results of C2C12 myotubes showed that garcinol treatment increased (p < 0.05) the transformation of glycolytic muscle fiber to oxidative muscle fiber by 45.9%. Garcinol treatment and p300 interference reduced (p < 0.05) the expression of fast MyHC but increased (p < 0.05) the expression of slow MyHC in vitro. Moreover, the acetylation of PGC-1α was significantly decreased (p < 0.05). Garcinol promotes the transformation of skeletal muscle fibers from the fast-glycolytic type to the slow-oxidative type through the p300/PGC-1α signaling pathway in C2C12 myotubes.
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Affiliation(s)
- Weilei Yao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Baoyin Guo
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Taimin Jin
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Zhengxi Bao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Tongxin Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Shu Wen
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Feiruo Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
- Correspondence: ; Tel.: +86-10-87286912; Fax: +86-10-87280408
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26
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Jun Q, Youhong L, Yuan Z, Xi Y, Wang B, Xinyi S, Fu Y, Kedan C, Lian J, Jianqing Z. Histone modification of endothelial-mesenchymal transition in cardiovascular diseases. Front Cardiovasc Med 2022; 9:1022988. [PMID: 36568553 PMCID: PMC9768231 DOI: 10.3389/fcvm.2022.1022988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial-mesenchymal transition (EndMT) is a differentiation process in which endothelial cells lose their own characteristics and acquire mesenchymal-like characteristics, which contributes to the formation and development of atherosclerotic plaques. Until now, there is still a lack of effective measures to treat atherosclerosis (AS), so there is an urgent need to understand the underlying mechanisms of AS. In addition, although various studies have shown that EndMT is involved in the pathological stages of cardiovascular diseases, such as myocardial fibrosis, myocardial hypertrophy, and hypertension, the specific molecular mechanisms driving EndMT are still in the exploratory stage. In this review, we review the role of histone modifications (methylation, demethylation and acetylation, deacetylation) on EndMT in cardiovascular disease, aiming to target histone-modifying enzymes to guide cardiovascular disease therapy.
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Affiliation(s)
- Qiu Jun
- Medicine School of Ningbo University, Ningbo, China
| | - Li Youhong
- Li Huili Hospital Affiliated to Ningbo University, Ningbo, China
| | - Zhong Yuan
- Ningbo Medical-Industrial Integration Innovation Research Institute, Ningbo, China
| | - Yang Xi
- Medicine School of Ningbo University, Ningbo, China
| | - Bingyu Wang
- Medicine School of Ningbo University, Ningbo, China
| | - Sun Xinyi
- Medicine School of Ningbo University, Ningbo, China
| | - Yin Fu
- Medicine School of Ningbo University, Ningbo, China
| | - Cen Kedan
- Medicine School of Ningbo University, Ningbo, China
| | | | - Zhou Jianqing
- Li Huili Hospital Affiliated to Ningbo University, Ningbo, China
- Medicine School of Ningbo University, Ningbo, China
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27
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An J, An S, Choi M, Jung JH, Kim B. Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery. Int J Mol Sci 2022; 23:13558. [PMID: 36362345 PMCID: PMC9657766 DOI: 10.3390/ijms232113558] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 02/02/2024] Open
Abstract
Esophageal cancer (EC) is one of the most malignant types of cancer worldwide and has a high incidence and mortality rate in Asian countries. When it comes to treating EC, although primary methods such as chemotherapy and surgery exist, the prognosis remains poor. The purpose of this current research is to review the range of effects that natural products have on cancer by analyzing studies conducted on EC. Fifty-seven studies were categorized into four anti-cancer mechanisms, as well as clinical trials. The studies that were scrutinized in this research were all reported within five years. The majority of the substances reviewed induced apoptosis in EC, acting on a variety of mechanisms. Taken together, this study supports the fact that natural products have the potential to act as a candidate for treating EC.
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Affiliation(s)
| | | | | | | | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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28
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Zhang Y, Dong F, Cao Z, Wang T, Pan L, Luo W, Ding W, Li J, Jin L, Liu H, Zhang H, Mu J, Han M, Wei Y, Deng X, Liu D, Hao P, Zeng G, Pang Y, Liu G, Zhen C. Eupalinolide A induces autophagy via the ROS/ERK signaling pathway in hepatocellular carcinoma cells in vitro and in vivo. Int J Oncol 2022; 61:131. [PMID: 36111510 PMCID: PMC9507091 DOI: 10.3892/ijo.2022.5421] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/17/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver. The current systemic drugs used to treat hepatocellular carcinoma result in low overall survival time. It has therefore been suggested that new small‑molecule drugs should be developed for treating hepatocellular carcinoma. Eupatorium lindleyanum DC. (EL) has been used to treat numerous diseases, particularly respiratory diseases; however, to the best of our knowledge, studies have not yet fully elucidated the effect of EL on hepatocellular carcinoma. In the present study, the effect of eupalinolide A (EA), one of the extracts of EL, was evaluated on tumor growth in a xenograft model of human hepatocellular carcinoma cells, and on the proliferation and migration of hepatocellular carcinoma cell lines. Cell cycle progression and the type of cell death were then evaluated using the Cell Counting Kit 8 assay, flow cytometry, electron microscopy and western blotting. EA significantly inhibited cell proliferation and migration by arresting the cell cycle at the G1 phase and inducing autophagy in hepatocellular carcinoma cells. EA‑induced autophagy was mediated by reactive oxygen species (ROS) and ERK signaling activation. Specific inhibitors of ROS, autophagy and ERK inhibited EA‑induced cell death and migration. In conclusion, the present study revealed that EA may inhibit the proliferation and migration of hepatocellular carcinoma cells, highlighting its potential as a promising antitumor compound for treating hepatocellular carcinoma.
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Affiliation(s)
- Yonghui Zhang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
- Hepatological Surgery Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, P.R. China
| | - Feng Dong
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Zhihao Cao
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Tingting Wang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Lian Pan
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Wujing Luo
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Wenxuan Ding
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Jiaxin Li
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Lishan Jin
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Huan Liu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Haoyang Zhang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Jinage Mu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Meiyue Han
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Yong Wei
- Key Laboratory of Intelligent Information Processing and Control, College of Electronic and Information Engineering, Chongqing Three Gorges University, Chongqing 404110, P.R. China
| | - Xuesong Deng
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Dan Liu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Po Hao
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Gang Zeng
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Yi Pang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
| | - Guiyuan Liu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
- General Surgery Department, The Affiliated Hospital of Chongqing Three Gorges Medical College, Chongqing 404000, P.R. China
| | - Changlin Zhen
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, P.R. China
- Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 404120, P.R. China
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The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection. Molecules 2022; 27:molecules27196234. [PMID: 36234768 PMCID: PMC9573598 DOI: 10.3390/molecules27196234] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022] Open
Abstract
Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.
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Shi XQ, Chen G, Tan JQ, Li Z, Chen SM, He JH, Zhang L, Xu HX. Total alkaloid fraction of Leonurus japonicus Houtt. Promotes angiogenesis and wound healing through SRC/MEK/ERK signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115396. [PMID: 35598796 DOI: 10.1016/j.jep.2022.115396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Leonurus japonicus Houtt., also known as motherwort, is a traditional Chinese medicine that was first identified in Shennong Bencao Jing, the first and essential pharmacy monograph in China. L. japonicus has been regarded as a good gynecological medicine since ancient times. It has been widely used in clinical settings for treatment of gynecological diseases and postnatal rehabilitation with good efficacy and low adverse effects. AIM OF THE STUDY The main purpose of this study was to determine the angiogenic and wound healing effects of total alkaloid fraction from L. japonicus Houtt. (TALH) in vivo and in vitro. In addition, the main bioactive components of total alkaloids were to be identified and analyzed in this study. MATERIALS AND METHODS First, the UHPLC/Q-TOF-MS method was used to identify and quantify the major components in the TALH extract. The wound healing activity was evaluated in vivo using a rat full-thickness cutaneous wound model. Histological study of wound healing in rat model was performed via immunohistochemistry and immunofluorescence. Cell proliferation was determined by MTT assay. Wound healing and transwell assays were used for detection of cell migration. The effect on tube formation was determined by tube formation assay in HUVECs. Western blot and RT-PCR were used to detect the expressions of relative proteins and genes respectively. Knock-down of SRC by siRNA was done to verify the crucial role of SRC in promotion of angiogenesis induced by TALH. RESULTS Seven characteristic peaks were recognized in the UHPLC/Q-TOF-MS spectrum, while four of the main components were quantified. The wound model in rats showed that treatment of TALH promoted wound healing by stimulating cellular proliferation and collagen deposition. In vitro experiments showed that co-treatment of TALH and VEGF increased cell proliferation, migration and tube formation in HUVECs. Mechanistic studies suggested that the co-treatment increased gene expressions of SRC, MEK1/2 and ERK1/2, as well as the phosphorylation levels of these proteins. Furthermore, the effect of co-treatment was attenuated after SRC knockdown, suggesting that SRC plays an important role in angiogenesis and wound healing induced by TALH and VEGF co-treatment. CONCLUSION Our results showed that TALH was one of the main active components of L. japonicus that promoted angiogenesis and wound healing by regulating the SRC/MEK/ERK pathway. Our study provided scientific basis for better clinical application of L. japonicas.
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Affiliation(s)
- Xiao-Qin Shi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Gan Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Jia-Qi Tan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Zhuo Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Si-Min Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Jia-Hui He
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Li Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China.
| | - Hong-Xi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Zhao J, Xu L, Dong Z, Zhang Y, Cao J, Yao J, Xing J. The LncRNA DUXAP10 Could Function as a Promising Oncogene in Human Cancer. Front Cell Dev Biol 2022; 10:832388. [PMID: 35186937 PMCID: PMC8850700 DOI: 10.3389/fcell.2022.832388] [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: 12/09/2021] [Accepted: 01/18/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer is one of the most prevalent and deadliest diseases globally, with an increasing morbidity of approximately 14 million new cancer cases per year. Identifying novel diagnostic and prognostic biomarkers for cancers is important for developing cancer therapeutic strategies and lowering mortality rates. Long noncoding RNAs (lncRNAs) represent a group of noncoding RNAs of more than 200 nucleotides that have been shown to participate in the development of human cancers. The novel lncRNA DUXAP10 was newly reported to be abnormally overexpressed in several cancers and positively correlated with poor clinical characteristics of cancer patients. Multiple studies have found that DUXAP10 widely regulates vital biological functions related to the development and progression of cancers, including cell proliferation, apoptosis, invasion, migration, and stemness, through different molecular mechanisms. The aim of this review was to recapitulate current findings regarding the roles of DUXAP10 in cancers and evaluate the potential of DUXAP10 as a novel biomarker for cancer diagnosis, treatment, and prognostic assessment.
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Affiliation(s)
- Junjie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lixia Xu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zihui Dong
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yize Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junhua Cao
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Yao
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiyuan Xing
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jiyuan Xing,
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Zheng J, Huang J, Liang Z. Acetyltransferase P300 Inhibits the Proliferation, Invasion, and Migration of Esophageal Cancer via Survivin Acetylation. Chin Med 2022. [DOI: 10.4236/cm.2022.134005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Rudrapal M, Khan J, Dukhyil AAB, Alarousy RMII, Attah EI, Sharma T, Khairnar SJ, Bendale AR. Chalcone Scaffolds, Bioprecursors of Flavonoids: Chemistry, Bioactivities, and Pharmacokinetics. Molecules 2021; 26:7177. [PMID: 34885754 PMCID: PMC8659147 DOI: 10.3390/molecules26237177] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 01/20/2023] Open
Abstract
Chalcones are secondary metabolites belonging to the flavonoid (C6-C3-C6 system) family that are ubiquitous in edible and medicinal plants, and they are bioprecursors of plant flavonoids. Chalcones and their natural derivatives are important intermediates of the flavonoid biosynthetic pathway. Plants containing chalcones have been used in traditional medicines since antiquity. Chalcones are basically α,β-unsaturated ketones that exert great diversity in pharmacological activities such as antioxidant, anticancer, antimicrobial, antiviral, antitubercular, antiplasmodial, antileishmanial, immunosuppressive, anti-inflammatory, and so on. This review provides an insight into the chemistry, biosynthesis, and occurrence of chalcones from natural sources, particularly dietary and medicinal plants. Furthermore, the pharmacological, pharmacokinetics, and toxicological aspects of naturally occurring chalcone derivatives are also discussed herein. In view of having tremendous pharmacological potential, chalcone scaffolds/chalcone derivatives and bioflavonoids after subtle chemical modification could serve as a reliable platform for natural products-based drug discovery toward promising drug lead molecules/drug candidates.
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Affiliation(s)
- Mithun Rudrapal
- Department of Pharmaceutical Chemistry, Rasiklal M. Dhariwal Institute of Pharmaceutical Education & Research, Pune 411019, India
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah 11952, Saudi Arabia; (J.K.); (R.M.I.I.A.)
- Health and Basic Sciences Research Center, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Abdul Aziz Bin Dukhyil
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah 11952, Saudi Arabia; (J.K.); (R.M.I.I.A.)
| | - Randa Mohammed Ibrahim Ismail Alarousy
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah 11952, Saudi Arabia; (J.K.); (R.M.I.I.A.)
- Department of Microbiology and Immunology, Division of Veterinary Researches, National Research Center, Giza 12622, Egypt
| | - Emmanuel Ifeanyi Attah
- Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka 410001, Nigeria;
| | - Tripti Sharma
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar 751003, India;
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Lv X, Xu G. Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers. World J Gastrointest Oncol 2021; 13:1648-1667. [PMID: 34853641 PMCID: PMC8603464 DOI: 10.4251/wjgo.v13.i11.1648] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.
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Affiliation(s)
- Xiaoqun Lv
- Department of Pharmacy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Sabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-β in Gastrointestinal Tumors. Cancers (Basel) 2021; 13:cancers13163960. [PMID: 34439114 PMCID: PMC8391793 DOI: 10.3390/cancers13163960] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The transforming growth factor β signaling pathway elicits a broad range of physiological re-sponses, and its misregulation has been related to cancer. The secreted cytokine TGFβ exerts a tumor-suppressive effect that counteracts malignant transformation. However, once tumor has developed, TGFβ can support tumor progression regulating epithelial to mesenchymal transition, invasion and metastasis, stimulating fibrosis, angiogenesis and immune suppression. Here we review the dichotomous role of TGF-β in the progression of gastrointestinal tumors, as well as its intricate crosstalk with other signaling pathways. We also discuss about the therapeutic strate-gies that are currently explored in clinical trials to counteract TGF-β functions. Abstract Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.
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Affiliation(s)
- Fabio Sabbadini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Monica Bertolini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena De Matteis
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, University of Bologna, 40126 Bologna, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
- Correspondence:
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Wang Y, Xie Q, Tan H, Liao M, Zhu S, Zheng LL, Huang H, Liu B. Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies. Pharmacol Res 2021; 173:105702. [PMID: 34102228 DOI: 10.1016/j.phrs.2021.105702] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/07/2021] [Accepted: 05/29/2021] [Indexed: 02/08/2023]
Abstract
Epigenetics mainly refers to covalent modifications to DNA or histones without affecting genomes, which ultimately lead to phenotypic changes in cells or organisms. Given the abundance of regulatory targets in epigenetic pathways and their pivotal roles in tumorigenesis and drug resistance, the development of epigenetic drugs holds a great promise for the current cancer therapy. However, lack of potent, selective, and clinically tractable small-molecule compounds makes the strategy to target cancer epigenetic pathways still challenging. Therefore, this review focuses on epigenetic pathways, small molecule inhibitors targeting DNA methyltransferase (DNMT) and small molecule inhibitors targeting histone modification (the main regulatory targets are histone acetyltransferases (HAT), histone deacetylases (HDACs) and histone methyltransferases (HMTS)), as well as the combination strategies of the existing epigenetic therapeutic drugs and more new therapies to improve the efficacy, which will shed light on a new clue on discovery of more small-molecule drugs targeting cancer epigenetic pathways as promising strategies in the future.
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Affiliation(s)
- Yi Wang
- Health Management Center, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, PR China
| | - Qiang Xie
- Department of Stomatology, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Huidan Tan
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Minru Liao
- Department of Stomatology, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Ling-Li Zheng
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Rd, Xindu Region, Chengdu 610500, PR China.
| | - Haixia Huang
- Oral & Maxillofacial Reconstruction and Regeneration Laboratory, Southwest Medical University, Luzhou, 646000, PR China; Department of Prosthodontics, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, PR China.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China.
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Michalkova R, Mirossay L, Gazdova M, Kello M, Mojzis J. Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones. Cancers (Basel) 2021; 13:cancers13112730. [PMID: 34073042 PMCID: PMC8198114 DOI: 10.3390/cancers13112730] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Despite the important progress in cancer treatment in the past decades, the mortality rates in some types of cancer have not significantly decreased. Therefore, the search for novel anticancer drugs has become a topic of great interest. Chalcones, precursors of flavonoid synthesis in plants, have been documented as natural compounds with pleiotropic biological effects including antiproliferative/anticancer activity. This article focuses on the knowledge on molecular mechanisms of antiproliferative action of chalcones and draws attention to this group of natural compounds that may be of importance in the treatment of cancer disease. Abstract Although great progress has been made in the treatment of cancer, the search for new promising molecules with antitumor activity is still one of the greatest challenges in the fight against cancer due to the increasing number of new cases each year. Chalcones (1,3-diphenyl-2-propen-1-one), the precursors of flavonoid synthesis in higher plants, possess a wide spectrum of biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer. A plethora of molecular mechanisms of action have been documented, including induction of apoptosis, autophagy, or other types of cell death, cell cycle changes, and modulation of several signaling pathways associated with cell survival or death. In addition, blockade of several steps of angiogenesis and proteasome inhibition has also been documented. This review summarizes the basic molecular mechanisms related to the antiproliferative effects of chalcones, focusing on research articles from the years January 2015–February 2021.
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Xia S, Yu W, Menden H, Younger ST, Sampath V. FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner. Front Cell Dev Biol 2021; 9:657662. [PMID: 34017833 PMCID: PMC8129010 DOI: 10.3389/fcell.2021.657662] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/12/2021] [Indexed: 12/26/2022] Open
Abstract
The innate immune response of pulmonary endothelial cells (EC) to lipopolysaccharide (LPS) induces Forkhead box protein C2 (FOXC2) activation through Toll Like Receptor 4 (TLR4). The mechanisms by which FOXC2 expression is regulated in lung EC under LPS stimulation remain unclear. We postulated that FOXC2 regulates its own expression in sepsis, and its transcriptional autoregulation directs lymphatic EC cell-fate decision. Bioinformatic analysis identified potential FOXC2 binding sites in the FOXC2 promoter. In human lung EC, we verified using chromatin immunoprecipitation (ChIP) and luciferase assays that FOXC2 bound to its own promoter and stimulated its expression after LPS stimulation. Chemical inhibition of histone acetylation by garcinol repressed LPS-induced histone acetylation in the FOXC2 promoter region, and disrupted LPS-mediated FOXC2 binding and transcriptional activation. CRISPR/dCas9/gRNA directed against FOXC2-binding-element (FBE) suppressed LPS-stimulated FOXC2 binding and autoregulation by blocking FBEs in the FOXC2 promoter, and repressed expression of lymphatic EC markers. In a neonatal mouse model of sterile sepsis, LPS-induced FOXC2 binding to FBE and FOXC2 expression in lung EC was attenuated with garcinol treatment. These data reveal a new mechanism of LPS-induced histone acetylation-dependent FOXC2 autoregulation.
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Affiliation(s)
- Sheng Xia
- Department of Pediatrics, Children's Mercy Kansas City, MO, United States
| | - Wei Yu
- Department of Pediatrics, Children's Mercy Kansas City, MO, United States
| | - Heather Menden
- Department of Pediatrics, Children's Mercy Kansas City, MO, United States
| | - Scott T Younger
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, MO, United States
| | - Venkatesh Sampath
- Department of Pediatrics, Children's Mercy Kansas City, MO, United States
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Zaidi SAH, Thakore N, Singh S, Guzman W, Mehrotra S, Gangaraju V, Husain S. Histone Deacetylases Regulation by δ-Opioids in Human Optic Nerve Head Astrocytes. Invest Ophthalmol Vis Sci 2021; 61:17. [PMID: 32915982 PMCID: PMC7488628 DOI: 10.1167/iovs.61.11.17] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose We determined whether δ-opioid receptor agonist (SNC-121) regulates acetylation homeostasis via controlling histone deacetylases (HDACs) activity and expression in optic nerve head (ONH) astrocytes. Methods ONH astrocytes were treated with SNC-121 (1 µM) for 24 hours. The HDAC activity was measured using HDAC-specific fluorophore-conjugated synthetic substrates, Boc-Lys(Ac)-AMC and (Boc-Lys(Tfa)-AMC). Protein and mRNA expression of each HDAC was determined by Western blotting and quantitative real-time PCR. IOP in rats was elevated by injecting 2.0 M hypertonic saline into the limbal veins. Results Delta opioid receptor agonist, SNC-121 (1 µM), treatment increased acetylation of histone H3, H2B, and H4 by 128 ± 3%, 45 ± 1%, and 68 ± 2%, respectively. The addition of Garcinol, a histone-acetyltransferase inhibitor, fully blocked SNC-121–induced histone H3 acetylation. SNC-121 reduced the activities of class I and IIb HDACs activities significantly (17 ± 3%) and this decrease in HDACs activities was fully blocked by a selective δ-opioid receptors antagonist, naltrindole. SNC-121 also decrease the mRNA expression of HDAC-3 and HDAC-6 by 19% and 18%, respectively. Furthermore, protein expression of HDAC 1, 2, 3, and 6 was significantly (P < 0.05) decreased by SNC-121 treatment. SNC-121 treatment also reduced lipopolysaccharide-induced TNF-α production from ONH astrocytes and glial fibrillary acidic protein immunostaining in the optic nerve of ocular hypertensive animals. Conclusions We provided evidence that δ-opioid receptor agonist activation increased histone acetylation, decrease HDACs class I and class IIb activities, mRNA, and protein expression, lipopolysaccharide-induced TNF-α production in ONH astrocytes. Our data also demonstrate that SNC-121 treatment decrease glial fibrillary acidic protein immunostaining in the optic nerves of animals with ocular hypertension.
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Affiliation(s)
- Syed A H Zaidi
- Hewitt Laboratory of the Ola B. Williams Glaucoma Centre, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina
| | - Nakul Thakore
- Hewitt Laboratory of the Ola B. Williams Glaucoma Centre, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina
| | - Sudha Singh
- Hewitt Laboratory of the Ola B. Williams Glaucoma Centre, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina
| | - Wendy Guzman
- Hewitt Laboratory of the Ola B. Williams Glaucoma Centre, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina
| | - Shikhar Mehrotra
- Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
| | - Vamsi Gangaraju
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
| | - Shahid Husain
- Hewitt Laboratory of the Ola B. Williams Glaucoma Centre, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina
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Garcinol-A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug. Int J Mol Sci 2021; 22:ijms22062828. [PMID: 33799504 PMCID: PMC8001519 DOI: 10.3390/ijms22062828] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/04/2021] [Accepted: 03/06/2021] [Indexed: 12/11/2022] Open
Abstract
Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.
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Development of a New Nanocarrier for Dietary Garcinol: Characterization and In Vitro Efficacy Evaluation Using Breast Cancer Stem Cells Grown in Hypoxia. J FOOD QUALITY 2021. [DOI: 10.1155/2021/6654211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Garcinol (GA), a polyisoprenylated benzophenone derivative, is one of the major phytochemicals found in a number of fruits of Garcinia. This study aimed to develop a new nanodelivery system comprising GA, hyaluronic acid (HA), and poly(lactic-co-glycolic acid) (PLGA) to actively target breast cancer stem cells (bCSCs) grown under hypoxic conditions. HA has been reported to show higher affinity for the cluster-determinant 44 receptor (CD44), while PLGA is an FDA-approved biodegradable polymer used in clinical applications. Nanoparticles (NPs) were prepared by emulsion solvent diffusion technique using DMAB as the emulsifier. Following preparation, particle size, surface charge, and polydispersity index of NPs were characterized. Antiproliferative effects of NPs were assessed by the WST-1 cell proliferation assay. Apoptotic effects of NPs were evaluated by the caspase-3/7 assay. Effects of prepared NPs on the expression of genes related to hypoxia-inducing factors (HIF-1α and HIF-2α) and notch ligands (DLL1 and Jagged1) were evaluated using real-time PCR. HA-coated garcinol-loaded NPs (HA-GA-NPs) showed greater antiproliferative effects in bCSCs grown under hypoxia. Moreover, HA-GA-NPs showed an improved cellular uptake via receptor-mediated endocytosis compared to non-HA-coated GA-NPs. Exposure to GA-HA-NPs resulted in a significant downregulation in hypoxia-inducing factors and notch pathway-related genes. Activation of caspase-3/7 confirmed the HA-GA-NPs can induce apoptosis in bCSCs. Overall findings of the study confirm that HA-GA-NPs can be considered as an effective nanodelivery system to target bCSCs grown under the hypoxic microenvironment.
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Anticancer activities of TCM and their active components against tumor metastasis. Biomed Pharmacother 2020; 133:111044. [PMID: 33378952 DOI: 10.1016/j.biopha.2020.111044] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, slight side effects and good therapeutic effects. Good anti-tumor effects are shown by Traditional Chinese Medicine prescription, Chinese patent medicine, single Traditional Chinese Medicine and Traditional Chinese medicine monomer compound. Clinically, TCM prolonged the survival time of patients and improved the life quality of patients, due to less side effects. Cancer metastasis is a complex process involving numerous steps, multiple genes and their products. During the process of tumor metastasis, firstly, cancer cell increases its proliferative capacity by reducing autophagy and apoptosis, and then the cancer cell capacity is stimulated by increasing the ability of tumors to absorb nutrients from the outside through angiogenesis. Both of the two steps can increase tumor migration and invasion. Finally, the purpose of tumor metastasis is achieved. By inhibiting autophagy and apoptosis of tumor cells, angiogenesis and EMT outside the tumor can inhibit the invasion and migration of cancer, and consequently achieve the purpose of inhibiting tumor metastasis. This review explores the research achievements of Traditional Chinese Medicine on breast cancer, lung cancer, hepatic carcinoma, colorectal cancer, gastric cancer and other cancer metastasis in the past five years, summarizes the development direction of TCM on cancer metastasis research in the past five years and makes a prospect for the future.
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Montalvo-Casimiro M, González-Barrios R, Meraz-Rodriguez MA, Juárez-González VT, Arriaga-Canon C, Herrera LA. Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy. Front Oncol 2020; 10:605386. [PMID: 33312959 PMCID: PMC7708379 DOI: 10.3389/fonc.2020.605386] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022] Open
Abstract
Gene mutations are strongly associated with tumor progression and are well known in cancer development. However, recently discovered epigenetic alterations have shown the potential to greatly influence tumoral response to therapy regimens. Such epigenetic alterations have proven to be dynamic, and thus could be restored. Due to their reversible nature, the promising opportunity to improve chemotherapy response using epigenetic therapy has arisen. Beyond helping to understand the biology of the disease, the use of modern clinical epigenetics is being incorporated into the management of the cancer patient. Potential epidrug candidates can be found through a process known as drug repositioning or repurposing, a promising strategy for the discovery of novel potential targets in already approved drugs. At present, novel epidrug candidates have been identified in preclinical studies and some others are currently being tested in clinical trials, ready to be repositioned. This epidrug repurposing could circumvent the classic paradigm where the main focus is the development of agents with one indication only, while giving patients lower cost therapies and a novel precision medical approach to optimize treatment efficacy and reduce toxicity. This review focuses on the main approved epidrugs, and their druggable targets, that are currently being used in cancer therapy. Also, we highlight the importance of epidrug repurposing by the rediscovery of known chemical entities that may enhance epigenetic therapy in cancer, contributing to the development of precision medicine in oncology.
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Affiliation(s)
- Michel Montalvo-Casimiro
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | - Rodrigo González-Barrios
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | - Marco Antonio Meraz-Rodriguez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | | | - Cristian Arriaga-Canon
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | - Luis A. Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
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Coste C, Gérard N, Dinh CP, Bruguière A, Rouger C, Leong ST, Awang K, Richomme P, Derbré S, Charreau B. Targeting MHC Regulation Using Polycyclic Polyprenylated Acylphloroglucinols Isolated from Garcinia bancana. Biomolecules 2020; 10:biom10091266. [PMID: 32887413 PMCID: PMC7563419 DOI: 10.3390/biom10091266] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/25/2020] [Accepted: 08/28/2020] [Indexed: 12/15/2022] Open
Abstract
Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.
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Affiliation(s)
- Chloé Coste
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; (C.C.); (N.G.)
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
| | - Nathalie Gérard
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; (C.C.); (N.G.)
| | - Chau Phi Dinh
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
| | - Antoine Bruguière
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
| | - Caroline Rouger
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
| | - Sow Tein Leong
- Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; (S.T.L.); (K.A.)
| | - Khalijah Awang
- Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; (S.T.L.); (K.A.)
| | - Pascal Richomme
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
| | - Séverine Derbré
- SONAS, EA921, University of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, CEDEX 01, 49045 Angers, France; (C.P.D.); (A.B.); (C.R.); (P.R.)
- Correspondence: (S.D.); (B.C.); Tel.: +33-249-180-440 (S.D.); +33-240-087-416 (B.C.); Fax: +33-240-087-411 (B.C.)
| | - Béatrice Charreau
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; (C.C.); (N.G.)
- Correspondence: (S.D.); (B.C.); Tel.: +33-249-180-440 (S.D.); +33-240-087-416 (B.C.); Fax: +33-240-087-411 (B.C.)
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Bicyclic polyprenylated acylphloroglucinols and their derivatives: structural modification, structure-activity relationship, biological activity and mechanism of action. Eur J Med Chem 2020; 205:112646. [PMID: 32791400 DOI: 10.1016/j.ejmech.2020.112646] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/02/2020] [Accepted: 07/04/2020] [Indexed: 12/22/2022]
Abstract
Bicyclic polyprenylated acylphloroglucinols (BPAPs), the principal bioactive benzophenone products isolated from plants of genera Garcinia and Hypericum, have attracted noticeable attention from the synthetic and biological communities due to their fascinating chemical structures and promising biological activities. However, the potential drug interaction, undesired physiochemical properties and toxicity have limited their potential use and development. In the last decade, pharmaceutical research on the structural modifications, structure-activity relationships (SARs) and mechanisms of action of BPAPs has been greatly developed to overcome the challenges. A comprehensive review of these scientific literature is extremely needed to give an overview of the rapidly emerging area and facilitate research related to BPAPs. This review, containing over 226 references, covers the progress made in the chemical synthesis-based structure modifications, SARs and the mechanism of action of BPAPs in vivo and vitro. The most relevant articles will focus on the discovery of lead compounds via synthetic modifications and the important BPAPs for which the direct targets have been deciphered. From this review, several key points of the SARs and mode of actions of this novel class of compounds have been summarized. The perspective and future direction of the research on BPAPs are concluded. This review would be helpful to get a better grasp of medicinal research of BPAPs and become a compelling guide for chemists dedicated to the synthesis of these compounds.
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Zhang J, Fang H, Zhang J, Guan W, Xu G. Garcinol Alone and in Combination With Cisplatin Affect Cellular Behavior and PI3K/AKT Protein Phosphorylation in Human Ovarian Cancer Cells. Dose Response 2020; 18:1559325820926732. [PMID: 32489337 PMCID: PMC7238453 DOI: 10.1177/1559325820926732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/15/2020] [Accepted: 04/17/2020] [Indexed: 11/15/2022] Open
Abstract
Garcinol is a plant-derived compound that has some physiological benefits to human cells. However, the effect of garcinol on ovarian cancer (OC) cell proliferation and apoptosis is unknown. The current study aimed to examine the effects of garcinol alone and in combination with cisplatin (DDP) on cellular behavior and to explore the expression pattern of PI3K/AKT and nuclear factor-κB (NF-κB) in human OC cells. We found that OVCAR-3 cell viability was decreased after garcinol treatment. Garcinol alone and in combination with DDP significantly inhibited cell proliferation and had a synergistic effect evaluated by CompuSyn software. The cell cycle analysis showed the S phase arrest by garcinol. Furthermore, garcinol alone and in combination with DDP promoted cell apoptosis. The garcinol-induced apoptosis was further confirmed by the detection of cleavage forms of PARP and caspase 3. An increase in proapoptotic factor Bax expression was also found in garcinol-treated cells. Moreover, garcinol significantly decreased the phosphorylation of PI3K and AKT proteins and downregulated the expression of NF-κB. Thus, our data demonstrated that garcinol has the potential to be used as an anticancer agent and may synergize the effect of DDP. These actions are most likely through the regulation of the PI3K/AKT and NF-κB pathways.
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Affiliation(s)
- Jie Zhang
- Department of Clinical Nutrition, Jinshan Hospital, Fudan University, Shanghai, China
| | - Huan Fang
- Department of Clinical Pharmacy, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jinguo Zhang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, China
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, China
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Aggarwal V, Tuli HS, Kaur J, Aggarwal D, Parashar G, Chaturvedi Parashar N, Kulkarni S, Kaur G, Sak K, Kumar M, Ahn KS. Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells. Biomedicines 2020; 8:103. [PMID: 32365899 PMCID: PMC7277375 DOI: 10.3390/biomedicines8050103] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab 160012, India;
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India; (D.A.); or (G.P.); (N.C.P.)
| | - Jagjit Kaur
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics (CNBP), Faculty of Engineering, The University of New South Wales, Sydney 2052, Australia;
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India; (D.A.); or (G.P.); (N.C.P.)
| | - Gaurav Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India; (D.A.); or (G.P.); (N.C.P.)
| | - Nidarshana Chaturvedi Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India; (D.A.); or (G.P.); (N.C.P.)
| | - Samruddhi Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vileparle-West, Mumbai 400056, India; (S.K.); (G.K.)
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS, Vileparle-West, Mumbai 400056, India; (S.K.); (G.K.)
| | | | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur 133001, India;
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
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Moreira-Silva F, Camilo V, Gaspar V, Mano JF, Henrique R, Jerónimo C. Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment? Pharmaceutics 2020; 12:E410. [PMID: 32365701 PMCID: PMC7284583 DOI: 10.3390/pharmaceutics12050410] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 12/24/2022] Open
Abstract
Epigenetic alterations, as a cancer hallmark, are associated with cancer initiation, progression and aggressiveness. Considering, however, that these alterations are reversible, drugs that target epigenetic machinery may have an inhibitory effect upon cancer treatment. The traditional drug discovery pathway is time-consuming and expensive, and thus, new and more effective strategies are required. Drug Repurposing (DR) comprises the discovery of a new medical indication for a drug that is approved for another indication, which has been recalled, that was not accepted or failed to prove efficacy. DR presents several advantages, mainly reduced resources, absence of the initial target discovery process and the reduced time necessary for the drug to be commercially available. There are numerous old drugs that are under study as repurposed epigenetic inhibitors which have demonstrated promising results in in vitro tumor models. Herein, we summarize the DR process and explore several repurposed drugs with different epigenetic targets that constitute promising candidates for cancer treatment, highlighting their mechanisms of action.
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Affiliation(s)
- Filipa Moreira-Silva
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (F.M.-S.); (V.C.)
| | - Vânia Camilo
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (F.M.-S.); (V.C.)
| | - Vítor Gaspar
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal; (V.G.); (J.F.M.)
| | - João F. Mano
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal; (V.G.); (J.F.M.)
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP) and Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal;
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (F.M.-S.); (V.C.)
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Shen G, Gao Q, Liu F, Zhang Y, Dai M, Zhao T, Cheng M, Xu T, Jin P, Yin W, Huang D, Weng H, Chen W, Ren H, Mu X, Wu X, Hu S. The Wnt3a/β-catenin/TCF7L2 signaling axis reduces the sensitivity of HER2-positive epithelial ovarian cancer to trastuzumab. Biochem Biophys Res Commun 2020; 526:685-691. [PMID: 32248976 DOI: 10.1016/j.bbrc.2020.03.154] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 03/26/2020] [Indexed: 12/24/2022]
Abstract
Epithelial ovarian cancer (EOC) is one of the most common and lethal gynecological cancers. Novel therapeutic agents have been developed for EOC, but patient survival remains poor. Trastuzumab has been approved for breast and gastric cancers with high expression of human epidermal growth factor receptor 2 (HER2), but it has not achieved any clinical success in EOC. Dysregulated Wnt/β-catenin signaling is involved in cancer development, but whether it plays a role in EOC resistance to trastuzumab remains largely unknown. Here, we observed that high expression of Wnt3a, β-catenin and TCF7L2, which can form a signaling axis in the Wnt/β-catenin pathway, commonly existed in HER2-positive EOC tissue samples and was correlated with a poor patient prognosis. Cell proliferation and migration assays and nude mouse xenograft model experiments demonstrated that the Wnt3a/β-catenin/TCF7L2 signaling axis promoted tumor cell growth and metastasis and reduced tumor sensitivity to trastuzumab. Analysis of downstream Akt signaling suggested that the function of the Wnt3a/β-catenin/TCF7L2 signaling axis was mediated, at least in part, through increasing Akt phosphorylation. Overall, this study reveals a crucial role for the Wnt3a/β-catenin/TCF7L2 signaling axis in EOC resistance to trastuzumab and the potential application of HER2-targeted drugs combined with inhibitors of this signaling axis for EOC treatment.
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Affiliation(s)
- Guodong Shen
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China.
| | - Qian Gao
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui, 230032, China
| | - Fenfen Liu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Yan Zhang
- Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; School of Health Services Management, Anhui Medical University, Hefei, Anhui, 230032, China
| | - Meng Dai
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Tingting Zhao
- Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Gynecology and Obstetrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Min Cheng
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Tingjuan Xu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Peipei Jin
- Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Wu Yin
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Dabing Huang
- Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China; Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Haiyan Weng
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Wen Chen
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Huirong Ren
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Xuanxuan Mu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Xinchun Wu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China
| | - Shilian Hu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, 230001, China.
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