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Ansari MM, Yadav V, Dighe S, Kuche K, Kanika, Khan R, Jain S. Co-Delivery of Glycyrrhizin and Paclitaxel via Gelatin-Based Core-Shell Nanoparticles Ameliorates 1,2-Dimethylhydrazine-Induced Precancerous Lesions in Colon. ACS Biomater Sci Eng 2025; 11:942-957. [PMID: 39865570 DOI: 10.1021/acsbiomaterials.4c02220] [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] [Indexed: 01/28/2025]
Abstract
Colorectal cancer is a lethal malignancy that begins from acquired/inherent premalignant lesions. Thus, targeting these lesions at an early stage of the disease could impede the oncogenesis and maximize the efficacy. The present work underscores a combinatorial therapy of paclitaxel (PTX) and glycyrrhizin (GL) delivered via gelatin-derived core-shell nanoparticles [AC-PCL(GL + PTX)-GNPs] for effective management of precancerous lesions. The desolvation method was adopted to prepare GL-loaded gelatin nanoparticles (GL-GNPs), which were coated with PTX and AC-PCL. The prepared NPs exhibited optimal physical attributes and had spherical morphology, as analyzed by transmission electron microscopy and field-emission scanning electron microscopy. In vitro release studies revealed sustained release for ∼96 h. Cell culture studies in HTC 116, and HT-29 cells showed synergistic action with CI < 0.9 and DRI > 1. Moreover, AC-PCL(GL + PTX)-GNPs exhibited amplified intracellular uptake and thus significantly reduced IC50. Pharmacokinetic studies revealed substantiated pharmacokinetic parameters (AUC0-∞, Cmax, etc.). In vivo studies in a 1,2-dimethyl hydrazine-induced model revealed a decrease in the number of lesions, mucin depletion, and subside infiltrations. An immunohistochemical study revealed elevated expression of caspase-9 and suppressed expression of VEGF and Ki-67. Toxicity studies showed insignificant changes in systemic biomarkers along with no alterations in organ morphology and hemocompatibility. In essence, AC-PCL(GL + PTX)-GNPs render a competent and safer tactic to regulate early-stage precancerous lesions.
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Affiliation(s)
- Md Meraj Ansari
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar, Mohali, Punjab 160062, India
| | - Vivek Yadav
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar, Mohali, Punjab 160062, India
| | - Sayali Dighe
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar, Mohali, Punjab 160062, India
| | - Kaushik Kuche
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar, Mohali, Punjab 160062, India
| | - Kanika
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector-81, S.A.S. Nagar, Mohali, Punjab 140306, India
| | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector-81, S.A.S. Nagar, Mohali, Punjab 140306, India
| | - Sanyog Jain
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar, Mohali, Punjab 160062, India
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YIN YUQIN, WU YU, HUANG HONGLIANG, DUAN YINGYING, YUAN ZHONGWEN, CAO LIHUI, YING JINJIN, ZHOU YONGHENG, FENG SENLING. The superiority of PMFs on reversing drug resistance of colon cancer and the effect on aerobic glycolysis-ROS-autophagy signaling axis. Oncol Res 2024; 32:1891-1902. [PMID: 39574478 PMCID: PMC11576955 DOI: 10.32604/or.2024.048778] [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: 12/18/2023] [Accepted: 02/28/2024] [Indexed: 11/24/2024] Open
Abstract
Background Polymethoxylated flavones (PMFs) are compounds present in citrus peels and other Rutaceae plants, which exhibit diverse biological activities, including robust antitumor and antioxidant effects. However, the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown. In the present study, we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs. Methods MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo; the mRNA and protein levels of the target were detected by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) and Western blot protein immunoblotting (WB); An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo; The extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were detected to assess the cellular oxygen consumption rate and glycolytic process. Results HCT8/T cells demonstrated significant resistance to PTX, up-regulating the expression levels of ABCB1 mRNA, P-gp, LC3-I, and LC3-II protein, and increasing intracellular reactive oxygen species (ROS) content. PMFs mainly contain two active ingredients, nobiletin, and tangeretin, which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner. PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly. PMFs combined with PTX reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in HCT8/T cells. Additionally, PMFs reduced intracellular ROS content, down-regulated the expression levels of autophagy-related proteins LC3-I, LC3-II, Beclin1, and ATG7, and significantly reduced the number of autophagosomes in HCT8/T cells. Conclusions The present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis, which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.
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Affiliation(s)
- YUQIN YIN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YU WU
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - HONGLIANG HUANG
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YINGYING DUAN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - ZHONGWEN YUAN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - LIHUI CAO
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - JINJIN YING
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YONGHENG ZHOU
- Department of Pharmacy, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511300, China
| | - SENLING FENG
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
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Tang Z, Zhang N, Chen S, Fang J, Tang X, Lou Y, Jiang Y, Ma Y, Chen X, Chen Z, Zhan S, Ding X, Ding W, Ma Z. Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer. J Med Chem 2024. [PMID: 39054645 DOI: 10.1021/acs.jmedchem.4c01323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.
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Affiliation(s)
- Zhen Tang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Ningjing Zhang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Shuang Chen
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Jiebin Fang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Xinyi Tang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Yijie Lou
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yongjun Jiang
- College of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316021, China
| | - Yijun Ma
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Xiaoming Chen
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Zhe Chen
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Shuai Zhan
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Xia Ding
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Wanjing Ding
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
- Hainan Institute of Zhejiang University, Sanya 572025, China
| | - Zhongjun Ma
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
- Hainan Institute of Zhejiang University, Sanya 572025, China
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Liu X, Xu W, Li L, Zhang Z, Lu M, Xia X. Dual PI3K/mTOR Inhibitor BEZ235 combined with BMS-1166 Promoting Apoptosis in Colorectal Cancer. Int J Med Sci 2024; 21:1814-1823. [PMID: 39113885 PMCID: PMC11302559 DOI: 10.7150/ijms.84320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/27/2024] [Indexed: 08/10/2024] Open
Abstract
Background: BMS-1166, a PD-1/PD-L1 inhibitor, inhibits the binding of PD-L1 to PD-1, restores T cell function, and enhances tumor immune response. However, mutations in the tumor suppressor or impaired cellular signaling pathways may also lead to cellular transformation. In this study, the SW480 and SW480R cell lines were used as the model to elucidate the treatment with BMS-1166, BEZ235, and their combination. Methods: MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis were analyzed by flow cytometry. The phosphorylation level of the key kinases in the PI3K/Akt/mTOR and MAPK pathways, PD-L1, and the protein levels related to the proliferation, migration, and apoptosis were assessed using western blotting. Results: BEZ235 enhanced BMS-1166-mediated cell proliferation and migration inhibition in SW480 and SW480R cells and promoted apoptosis. Interestingly, the downregulation of the negative regulator PTEN raised the PD-L1 level, which was abolished by the inhibition of Akt. BMS-1166 promoted PI3K, Akt, mTOR, and Erk phosphorylation. However, the combination of BEZ235 with BMS-1166 suppressed the expression of PI3K, p-Akt, p-mTOR, and p-Erk in SW480 and SW480R cells compared to BMS-1166 or BEZ235 single treatment by inhibiting the binding of PD1 to PD-L1. Conclusions: PD-1 binds to PD-L1 and activates the PI3K/mTOR and MAPK pathways, which might be the molecular mechanism of acquired resistance of CRC to BMS-1166. The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.
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Affiliation(s)
| | | | | | | | | | - Xiaoping Xia
- Department of Clinical Laboratory, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China, 322000
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Miao X, Jiang P, Zhang X, Li X, Wu Z, Jiang Y, Liu H, Xie W, Li X, Shi B, Cai J, Gong W. Lactobacillus rhamnosus HN001 facilitates the efficacy of dual PI3K/mTOR inhibition prolonging cardiac transplant survival and enhancing antitumor effect. Microbiol Spectr 2024; 12:e0183923. [PMID: 38564670 PMCID: PMC11064485 DOI: 10.1128/spectrum.01839-23] [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: 05/02/2023] [Accepted: 11/24/2023] [Indexed: 04/04/2024] Open
Abstract
Solid organ transplantation is a crucial treatment for patients who have reached the end stage of heart, lung, kidney, or liver failure. However, the likelihood of developing cancer post-transplantation increases. Additionally, primary malignant tumors remain a major obstacle to the long-term survival of transplanted organs. Therefore, it is essential to investigate effective therapies that can boost the immune system's ability to combat cancer and prevent allograft rejection. We established a mouse orthotopic liver tumor model and conducted allogeneic heterotopic heart transplantation. Various treatments were administered, and survival curves were generated using the Kaplan-Meier method. We also collected graft samples and measured inflammatory cytokine levels in the serum using an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 to primary liver cancer model mice with cardiac allografts. Consistent with our prior findings, L. rhamnosus HN001 alleviated the intestinal flora imbalance caused by BEZ235. Our previous research confirmed that the combination of BEZ235 and L. rhamnosus HN001 significantly prolonged cardiac transplant survival. IMPORTANCE We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.
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Affiliation(s)
- Xiaolong Miao
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Peng Jiang
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaotong Zhang
- Medical department, Qingdao Eighth People’s Hospital, Qingdao, China
| | - Xinqiang Li
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zelai Wu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuancong Jiang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Han Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weixun Xie
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinwei Li
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bingfeng Shi
- Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jinzhen Cai
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
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Patel D, Sethi N, Patel P, Shah S, Patel K. Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review. Eur J Pharm Biopharm 2024; 198:114267. [PMID: 38514020 DOI: 10.1016/j.ejpb.2024.114267] [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: 11/24/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.
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Affiliation(s)
- Dhvani Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Nutan Sethi
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Paresh Patel
- Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Shreeraj Shah
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Kaushika Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India.
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Mou Y, Chen Y, Fan Z, Ye L, Hu B, Han B, Wang G. Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer. Bioorg Chem 2024; 146:107327. [PMID: 38579616 DOI: 10.1016/j.bioorg.2024.107327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/07/2024]
Abstract
Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.
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Affiliation(s)
- Yi Mou
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Yanmei Chen
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhichao Fan
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liansong Ye
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Bing Hu
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Guan Wang
- Department of Gastroenterology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Cao R, Guo S, Min L, Li P. Roles of Rictor alterations in gastrointestinal tumors (Review). Oncol Rep 2024; 51:37. [PMID: 38186315 PMCID: PMC10807360 DOI: 10.3892/or.2024.8696] [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: 04/05/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024] Open
Abstract
Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re‑sensitization of therapy‑resistant cancers to be made possible.
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Affiliation(s)
- Ruizhen Cao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Shuilong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
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Liu Y, Zhang Y, Yan Q, Zhong X, Hu C. Evaluation of microstructure, dissolution rate, and oral bioavailability of paclitaxel poloxamer 188 solid dispersion. Drug Deliv Transl Res 2024; 14:329-341. [PMID: 37578648 DOI: 10.1007/s13346-023-01400-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2023] [Indexed: 08/15/2023]
Abstract
Poor solubility is a major challenge for enhancing the oral bioavailability and clinical application of many drugs, including the broad-spectrum chemotherapy drug paclitaxel (PTX). A practical approach to improving the solubility of insoluble drugs is through the use of solid dispersion (SD). This study aimed to investigate the potential of the triblock copolymer, poloxamer 188 (P188), as a carrier for preparing solid dispersion of paclitaxel using spray drying technology. We systematically studied its microstructure, dissolution behavior in vitro, and pharmacokinetics. Our findings demonstrate that PTX exists in an amorphous state in copolymer composed of polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO) P188, with stronger miscibility with hydrophobic PPO segments. All three in vitro dissolution models revealed that the release rate of drugs in SD was significantly higher compared to that of physical mixtures (PM) as well as raw drugs. Furthermore, our pharmacokinetic results showed that the area under the curve(AUC) of PTX in SD was 6 times higher than that of active pharmaceutical ingredient(API), 4.5 times higher than PM, and the highest blood drug concentration (Cmax) reached 357.51 ± 125.54 (ng/mL), approximately 20 times higher than API. Overall, our findings demonstrate that the dissolution rate of amorphous PTX in SD significantly improves, effectively enhancing the oral bioavailability of PTX.
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Affiliation(s)
- Yao Liu
- Medical College, Qinghai University, Xining, 810001, Qinghai, People's Republic of China
| | - Yong Zhang
- Medical College, Qinghai University, Xining, 810001, Qinghai, People's Republic of China
| | - Qiuli Yan
- Medical College, Qinghai University, Xining, 810001, Qinghai, People's Republic of China
| | - Xueping Zhong
- Medical College, Qinghai University, Xining, 810001, Qinghai, People's Republic of China
| | - Chunhui Hu
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810001, Qinghai, People's Republic of China.
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10
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Jahandideh A, Yarizadeh M, Noei-Khesht Masjedi M, Fatehnejad M, Jahandideh R, Soheili R, Eslami Y, Zokaei M, Ahmadvand A, Ghalamkarpour N, Kumar Pandey R, Nabi Afjadi M, Payandeh Z. Macrophage's role in solid tumors: two edges of a sword. Cancer Cell Int 2023; 23:150. [PMID: 37525217 PMCID: PMC10391843 DOI: 10.1186/s12935-023-02999-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023] Open
Abstract
The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants-namely, melanoma, colon, glioma, and breast cancers.
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Affiliation(s)
- Arian Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- Usern Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahsa Yarizadeh
- Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Maryam Noei-Khesht Masjedi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Fatehnejad
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Romina Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roben Soheili
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Yeganeh Eslami
- Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardavan Ahmadvand
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nogol Ghalamkarpour
- Department of Clinical Laboratory Sciences, School of Allied Medicine, Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Rajan Kumar Pandey
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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11
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Abo-Zaid OAR, Moawed FSM, Barakat WEM, Ghobashy MM, Ahmed ESA. Antitumor activity of 5-fluorouracil polymeric nanogel synthesized by gamma radiation on a rat model of colon carcinoma: a proposed mechanism. Discov Oncol 2023; 14:138. [PMID: 37493814 PMCID: PMC10371941 DOI: 10.1007/s12672-023-00733-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/21/2023] [Indexed: 07/27/2023] Open
Abstract
The use of 5-fluorouracil (5-FU) is associated with multifaceted challenges and poor pharmacokinetics. Accordingly, our study was designed to prepare 5-FU nanogel as a new form of the colon cancer chemotherapeutic drug 5-FU using polyacrylic acid and gelatin hybrid nanogel as efficient drug carriers. Alongside the in vivo chemotherapeutic evaluation, the anti-proliferative and anti-apoptotic efficacy were carried out for 5-FU nanogel against 1,2-dimethylhydrazine (DMH, 20 mg/kg) and γ-radiation (4 Gy)-prompted colon dysplasia in rats compared to 5-FU. The morphology and size of 5-FU nanogel were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) in addition to cytotoxicity assay. The expression of phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR); Toll-like receptor2 (TLR2)/nuclear factor kappa B), adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream autophagy-related genes in addition to apoptotic markers were measured in colon tissues. Results: 5-FU nanogel reduced the levels of the TLR2/ NF-κβ as well as the expression of PI3K/AKT/mTOR. Moreover, it promoted autophagy through the activation of the AMPK and its downstream targets which consequently augmented the intrinsic and extrinsic apoptotic pathways. Conclusion: Collectively, these data might strengthen the therapeutic potential of 5-FU nanogel which can be used as an antitumor product for colon cancer.
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Affiliation(s)
- Omayma A R Abo-Zaid
- Biochemistry and Molecular Biology Department, Faculty of Vet. Med, Benha University, Benha, Egypt
| | - Fatma S M Moawed
- Health Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Cairo, 11787, Egypt.
| | - Wael E M Barakat
- Biochemistry and Molecular Biology Department, Faculty of Vet. Med, Benha University, Benha, Egypt
| | - Mohamed Mohamady Ghobashy
- Radiation Research of Polymer Chemistry Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Esraa S A Ahmed
- Radiation Biology Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
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12
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Albuquerque T, Neves AR, Paul M, Biswas S, Vuelta E, García-Tuñón I, Sánchez-Martin M, Quintela T, Costa D. A Potential Effect of Circadian Rhythm in the Delivery/Therapeutic Performance of Paclitaxel-Dendrimer Nanosystems. J Funct Biomater 2023; 14:362. [PMID: 37504857 PMCID: PMC10381694 DOI: 10.3390/jfb14070362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/29/2023] Open
Abstract
The circadian clock controls behavior and physiology. Presently, there is clear evidence of a connection between this timing system and cancer development/progression. Moreover, circadian rhythm consideration in the therapeutic action of anticancer drugs can enhance the effectiveness of cancer therapy. Nanosized drug delivery systems (DDS) have been demonstrated to be suitable engineered platforms for drug targeted/sustained release. The investigation of the chronobiology-nanotechnology relationship, i.e., timing DDS performance according to a patient's circadian rhythm, may greatly improve cancer clinical outcomes. In the present work, we synthesized nanosystems based on an octa-arginine (R8)-modified poly(amidoamine) dendrimer conjugated with the anticancer drug paclitaxel (PTX), G4-PTX-R8, and its physicochemical properties were revealed to be appropriate for in vitro delivery. The influence of the circadian rhythm on its cellular internalization efficiency and potential therapeutic effect on human cervical cancer cells (HeLa) was studied. Cell-internalized PTX and caspase activity, as a measure of induced apoptosis, were monitored for six time points. Higher levels of PTX and caspase-3/9 were detected at T8, suggesting that the internalization of G4-PTX-R8 into HeLa cells and apoptosis are time-specific/-regulated phenomena. For a deeper understanding, the clock protein Bmal1-the main regulator of rhythmic activity, was silenced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. Bmal1 silencing was revealed to have an impact on both PTX release and caspase activity, evidencing a potential role for circadian rhythm on drug delivery/therapeutic effect mediated by G4-PTX-R8.
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Affiliation(s)
- Tânia Albuquerque
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Ana Raquel Neves
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Milan Paul
- Department of Pharmacy, Nanomedicine Research Laboratory, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Swati Biswas
- Department of Pharmacy, Nanomedicine Research Laboratory, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Elena Vuelta
- Servicio de Transgénesis, Nucleus, Universidad de Salamanca, 37008 Salamanca, Spain
- IBSAL, Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain
- Departamento de Medicina, Universidad de Salamanca, 37008 Salamanca, Spain
| | - Ignacio García-Tuñón
- IBSAL, Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain
| | - Manuel Sánchez-Martin
- Servicio de Transgénesis, Nucleus, Universidad de Salamanca, 37008 Salamanca, Spain
- Departamento de Medicina, Universidad de Salamanca, 37008 Salamanca, Spain
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Instituto Biología Molecular y Celular del Cáncer (USAL/CSIC), 37007 Salamanca, Spain
| | - Telma Quintela
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
- UDI-IPG-Unidade de Investigação para o Desenvolvimento do Interior, Instituto Politécnico da Guarda, 6300-559 Guarda, Portugal
| | - Diana Costa
- CICS-UBI-Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
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13
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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14
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Effects of curcumin on 5-fluorouracil resistance of colon cancer cells through the PI3K/AKT/mTOR pathway via MACC1. Eur J Integr Med 2022. [DOI: 10.1016/j.eujim.2022.102202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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15
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Iqubal MK, Kaur H, Md S, Alhakamy NA, Iqubal A, Ali J, Baboota S. A technical note on emerging combination approach involved in the onconanotherapeutics. Drug Deliv 2022; 29:3197-3212. [PMID: 36226570 PMCID: PMC9578464 DOI: 10.1080/10717544.2022.2132018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Cancer is the second cause of mortality worldwide, and the currently available conventional treatment approach is associated with serious side effects and poor clinical outcomes. Based on the outcome of the exploratory preclinical and clinical studies, it was found that therapeutic response increases multiple folds when anticancer drugs are used in combination. However, the conventional combination of anticancer drugs was associated with various limitations such as increased cost of treatment, systemic toxicity, drug resistance, and reduced pharmacokinetic attributes. Hence, attempts were made to formulate nanocarrier fabricated combinatorial drugs (NFCDs) to effectively manage and treat cancer. This approach offers several advantages, such as improved stability, lower drug exposure, targeted drug delivery, low side effects, and improved clinical outcome. Hence, in this review, first time, we have discussed the recent advancement and various types of nano carrier-based combinatorial drug delivery systems in a different type of cancer and highlighted the personalized combinatorial theranostic medicine as a futuristic anticancer treatment approach.
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Affiliation(s)
- Mohammad Kashif Iqubal
- Product Development Department, Sentiss Research Centre, Sentiss Pharma Pvt Ltd, Gurugram, India.,Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Harsimran Kaur
- Department of Pharmaceutics, Delhi Pharmaceutical Science and Research University, New Delhi, India
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sanjula Baboota
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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16
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Choudhury AD. PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications. Prostate 2022; 82 Suppl 1:S60-S72. [PMID: 35657152 DOI: 10.1002/pros.24372] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/21/2022] [Accepted: 05/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite significant advances in molecular characterization and therapeutic targeting of advanced prostate cancer, it remains the second most common cause of cancer death in men in the United States. The PI3K (Phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin) signaling pathway is commonly altered in prostate cancer, most frequently through loss of the PTEN (Phosphatase and Tensin Homolog) tumor suppressor, and is critical for cancer cell proliferation, migration, and survival. METHODS This study summarizes signaling through the PTEN/PI3K pathway, alterations in pathway components commonly seen in advanced prostate cancer, and results of clinical trials of pathway inhibitors reported to date with a focus on more recently reported studies. It also reviews rationale for combination approaches currently under study, including with taxanes, immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors, and discusses future directions in biomarker testing and therapeutic targeting of this pathway. RESULTS Clinical trials studying pharmacologic inhibitors of PI3K, AKT or mTOR kinases have demonstrated modest activity of specific agents, with several trials of pathway inhibitors currently in progress. A key challenge is the importance of PI3K/AKT/mTOR signaling in noncancerous tissues, leading to predictable but often severe toxicities at therapeutic doses. RESULTS Further advances in selective pharmacologic inhibition of the PI3K/AKT/mTOR pathway in tumors, development of rational combinations, and appropriate biomarker selection to identify the appropriate tumor- and patient-specific vulnerabilities will be required to optimize clinical benefit from therapeutic targeting of this pathway.
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Affiliation(s)
- Atish D Choudhury
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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17
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Huang X, Cao Y, Bao P, Zhu B, Cheng Z. High expression of PI4K2A predicted poor prognosis of colon adenocarcinoma (COAD) and correlated with immunity. Cancer Med 2022; 12:837-851. [PMID: 35634680 PMCID: PMC9844633 DOI: 10.1002/cam4.4895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/26/2022] [Accepted: 05/15/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND PI4K2A has been found to have a tumor-promoting role in various solid tumors and be involved in various biological procedures. In this article, we aim to investigate the prognostic values of PI4K2A and provide new insights in colon adenocarcinoma (COAD). METHODS The Cancer Genome Atlas (TCGA) database, Human Protein Atlas online database, and UALCAN database were used to analyze the expression of PI4K2A in COAD and the survival of patients. Univariate and multifactorial Cox regression analyses were used to assess the prognosis of PI4K2A on COAD. GSEA was used to explore PI4K2A-related signaling pathways. In addition, the effect of PI4K2A on immune checkpoint inhibitors (ICIs) treatment was investigated by constructing a TIDE model and predicting the association between PI4K2A and anticancer drug sensitivity through the CellMiner database. RESULTS In the TCGA database, PI4K2A was highly expressed in COAD and the similar results were verified by qRT-PCR. Survival analysis, utilizing Kaplan-Meier curves, revealed that COAD patients with high PI4K2A expression had a worse prognosis. In addition, PI4K2A expression was discovered to have been associated with T-stage, N-stage, and pathological stage by logistic analysis. Next, we utilized univariate and multifactorial Cox regression analyses to identify PI4K2A as an independent predictor. Additionally, GSEA analysis indicates that PI4K2A is enriched in MAPK signaling pathway, Toll-like receptor signaling pathway, etc. In COAD, PI4K2A was remarkably associated with the tumor immune microenvironment. In addition, by constructing a TIDE model, we discovered that COAD patients in the PI4K2A low-expression cohort were better treated with ICI. Finally, analysis of the CellMiner database predicted that PI4K2A was adversely correlated with the sensitivity of various anticancer drugs. CONCLUSIONS Our study suggests that PI4K2A may be a potential predictor of poor prognosis in COAD and a potential biomarker for early diagnosis, prognosis, and treatment.
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Affiliation(s)
- Xinkun Huang
- Department of General SurgeryAffiliated Hospital of NantongNantongJiangsu ProvinceChina
| | - Yang Cao
- Department of OperationAffiliated Hospital of NantongNantongJiangsu ProvinceChina
| | - Peng Bao
- Department of Critical Care MedicineAffiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina
| | - Bingye Zhu
- Department of UrologyAffiliated Nantong Hospital of Shanghai University/The Sixth People's Hospital of NantongNantongJiangsu ProvinceChina
| | - Zhouyang Cheng
- Department of General SurgeryAffiliated Hospital of NantongNantongJiangsu ProvinceChina
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18
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Alrumaihi F, Khan MA, Babiker AY, Alsaweed M, Azam F, Allemailem KS, Almatroudi AA, Ahamad SR, Alsugoor MH, Alharbi KN, Almansour NM, Khan A. Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis. Molecules 2022; 27:molecules27072192. [PMID: 35408590 PMCID: PMC9000458 DOI: 10.3390/molecules27072192] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/19/2022] [Accepted: 03/25/2022] [Indexed: 02/07/2023] Open
Abstract
Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.
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Affiliation(s)
- Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Masood Alam Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Ali Yousif Babiker
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Mohammed Alsaweed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia;
| | - Faizul Azam
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia;
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Ahmad A. Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Syed Rizwan Ahamad
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Mahdi H. Alsugoor
- Department of Emergency Medical Services, Faculty of Health Sciences, AlQunfudah, Umm Al-Qura University, Makkah 21912, Saudi Arabia;
| | - Khloud Nawaf Alharbi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia;
| | - Arif Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
- Correspondence: ; Tel.: +966-590038460; Fax: +966-63801628
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19
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Wang Y, Miao X, Jiang Y, Wu Z, Zhu X, Liu H, Wu X, Cai J, Ding X, Gong W. The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma. Cell Death Dis 2022; 13:146. [PMID: 35165269 PMCID: PMC8844296 DOI: 10.1038/s41419-022-04583-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 11/30/2021] [Accepted: 01/24/2022] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) still ranks among the top cancers worldwide with high incidence and mortality. Due to abnormal activation of the PI3K/AKT/mTOR signalling pathway in HCC, targeting this pathway represents a potential therapeutic strategy. NVP-BEZ235 is a novel dual-targeted ATP-competitive PI3K/mTOR inhibitor that has shown effective antitumor effects. In this study, we found that interleukin-6 (IL-6) was significantly increased after exposure to NVP-BEZ235, and we proposed a treatment in which an anti-IL-6 antibody was combined with NVP-BEZ235 for HCC. In vitro results revealed that targeted inhibition of IL-6 potentiated the antitumor effects of NVP-BEZ235 in HCC cells. The mechanism might be attributed to their synergistic inhibitory activity on the PI3K/AKT/mTOR signalling pathway. Furthermore, an in vivo study demonstrated that combined administration of NVP-BEZ235 and anti-IL-6 Ab reduced HCC tumour load more effectively than either NVP-BEZ235 or anti-IL-6 Ab treatment alone. These findings add guidance value to the analysis of HCC and provide a reference for clinical treatment.
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Affiliation(s)
- Yao Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang, China
| | - Xiaolong Miao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yuancong Jiang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Zelai Wu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xuhang Zhu
- Department of head and neck Surgery, Zhejiang Cancer Hospital, Hangzhou, China
| | - Han Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiaoying Wu
- Department of Thyroid and Breast Surgery, Tongde Hospital of Zhejiang Province, Hangzhou City, China
| | - Jinzhen Cai
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China. .,Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang, China.
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, 310058, China. .,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
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20
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Zhang C, Zhou X, Zhang H, Han X, Li B, Yang R, Zhou X. Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer. Front Pharmacol 2022; 13:776895. [PMID: 35237155 PMCID: PMC8883114 DOI: 10.3389/fphar.2022.776895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Multidrug resistance (MDR) of tumors is one of the clinical direct reasons for chemotherapy failure. MDR directly leads to tumor recurrence and metastasis, with extremely grievous mortality. Engineering a novel nano-delivery system for the treatment of MDR tumors has become an important part of nanotechnology. Herein, this review will take those different mechanisms of MDR as the classification standards and systematically summarize the advances in nanotechnology targeting different mechanisms of MDR in recent years. However, it still needs to be seriously considered that there are still some thorny problems in the application of the nano-delivery system against MDR tumors, including the excessive utilization of carrier materials, low drug-loading capacity, relatively narrow targeting mechanism, and so on. It is hoped that through the continuous development of nanotechnology, nano-delivery systems with more universal uses and a simpler preparation process can be obtained, for achieving the goal of defeating cancer MDR and accelerating clinical transformation.
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Affiliation(s)
- Chengyuan Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xuemei Zhou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Hanyi Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xuanliang Han
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Baijun Li
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Ran Yang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xing Zhou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
- Department of Pharmacy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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21
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The Effect of Liposomal Diallyl Disulfide and Oxaliplatin on Proliferation of Colorectal Cancer Cells: In Vitro and In Silico Analysis. Pharmaceutics 2022; 14:pharmaceutics14020236. [PMID: 35213970 PMCID: PMC8877238 DOI: 10.3390/pharmaceutics14020236] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/24/2021] [Accepted: 01/13/2022] [Indexed: 01/27/2023] Open
Abstract
Diallyl disulfide (DADS) is one of the main bioactive organosulfur compounds of garlic, and its potential against various cancer models has been demonstrated. The poor solubility of DADS in aqueous solutions limits its uses in clinical application. The present study aimed to develop a novel formulation of DADS to increase its bioavailability and therapeutic potential and evaluate its role in combination with oxaliplatin (OXA) in the colorectal cancer system. We prepared and characterized PEGylated, DADS (DCPDD), and OXA (DCPDO) liposomes. The anticancer potential of these formulations was then evaluated in HCT116 and RKO colon cancer cells by different cellular assays. Further, a molecular docking-based computational analysis was conducted to determine the probable binding interactions of DADS and OXA. The results revealed the size of the DCPDD and DCPDO to be 114.46 nm (95% EE) and 149.45 nm (54% EE), respectively. They increased the sensitivity of the cells and reduced the IC50 several folds, while the combinations of them showed a synergistic effect and induced apoptosis by 55% in the cells. The molecular docking data projected several possible targets of DADS and OXA that could be evaluated more precisely by these novel formulations in detail. This study will direct the usage of DCPDD to augment the therapeutic potential of DCPDO against colon cancer in clinical settings.
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22
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Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers. Drug Deliv Transl Res 2022; 12:2550-2560. [PMID: 35031972 DOI: 10.1007/s13346-021-01106-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7 nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.
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23
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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24
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Nanotherapeutics approaches to overcome P-glycoprotein-mediated multi-drug resistance in cancer. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 40:102494. [PMID: 34775061 DOI: 10.1016/j.nano.2021.102494] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/08/2021] [Accepted: 10/27/2021] [Indexed: 12/19/2022]
Abstract
Multidrug resistance (MDR) in cancer chemotherapy is a growing concern for medical practitioners. P-glycoprotein (P-gp) overexpression is one of the major reasons for multidrug resistance in cancer chemotherapy. The P-gp overexpression in cancer cells depends on several factors like adenosine triphosphate (ATP) hydrolysis, hypoxia-inducible factor 1 alpha (HIF-1α), and drug physicochemical properties such as lipophilicity, molecular weight, and molecular size. Further multiple exposures of anticancer drugs to the P-gp efflux protein cause acquired P-gp overexpression. Unique structural and functional characteristics of nanotechnology-based drug delivery systems provide opportunities to circumvent P-gp mediated MDR. The primary mechanism behind the nanocarrier systems in P-gp inhibition includes: bypassing or inhibiting the P-gp efflux pump to combat MDR. In this review, we discuss the role of P-gp in MDR and highlight the recent progress in different nanocarriers to overcome P-gp mediated MDR in terms of their limitations and potentials.
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