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Zhu C, Wang C, Wang X, Dong S, Xu Q, Zheng J. PABPC1 silencing inhibits pancreatic cancer cell proliferation and EMT, and induces apoptosis via PI3K/AKT pathway. Cytotechnology 2024; 76:351-361. [PMID: 38736728 PMCID: PMC11082123 DOI: 10.1007/s10616-024-00626-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 03/11/2024] [Indexed: 05/14/2024] Open
Abstract
Pancreatic cancer is difficult to manage owing to the challenges involved in its treatment and nursing. This study aimed to clarify the roles and mechanisms of action of Poly (A)-binding protein cytoplasmic 1 (PABPC1) on pancreatic cancer. The expression of PABPC1 in pancreatic cancer tissues and cell lines was detected using RT-qPCR and western blotting. The effects of PABPC1 on proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and the PI3K/AKT signaling pathway in pancreatic cancer cells were further investigated using MTT assays, flow cytometry, and western blotting. The expression of PABPC1 was significantly upregulated in pancreatic cancer tissues and cells, whereas PABPC1 downregulation inhibited pancreatic cancer cell proliferation, induced apoptosis, decreased the expression of EMT-associated proteins, and exerted a regulatory effect by inhibiting the PI3K/AKT signaling pathway. In addition, the findings indicated that PABPC1 over-expression significantly promoted pancreatic cancer cell proliferation, inhibited apoptosis, decreased the expression of E-cadherin, enhanced N-cadherin expression, and activating the PI3K/AKT signaling pathway. PABPC1 silencing significantly inhibited proliferation and EMT and induced apoptosis in pancreatic cancer cells. These findings provide novel insights into the role of PABPC1 in the development of pancreatic cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-024-00626-1.
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Affiliation(s)
- Changren Zhu
- Pathology Department, Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, 225001 China
| | - Cuimei Wang
- Pathology Department, Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, 225001 China
| | - Xiaodong Wang
- Department of Biliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, 225001 China
| | - Shuangshuang Dong
- Pathology Department, Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, 225001 China
| | - Qing Xu
- Pathology Department, Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, 225001 China
| | - Jun Zheng
- Daytime Surgical Ward, Northern Jiangsu People’s Hospital of Jiangsu Province, No. 98 Nantong West Road, Yangzhou, 225001 China
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2
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Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, Kazeminejad A. VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives. Life Sci 2024; 345:122563. [PMID: 38508233 DOI: 10.1016/j.lfs.2024.122563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Armaghan Kazeminejad
- Department of Dermatology, Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences,Sari, Iran
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3
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Ye H, Yu W, Ni Y, Bao X, Zhang X, Li Y, Chen A, Li J, Zheng L. Apatinib plus chemotherapy is associated with an improved tumor response, survival and tolerance compared with chemotherapy alone for advanced lung adenocarcinoma treatment. Oncol Lett 2024; 27:194. [PMID: 38495832 PMCID: PMC10941069 DOI: 10.3892/ol.2024.14327] [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: 05/06/2023] [Accepted: 11/13/2023] [Indexed: 03/19/2024] Open
Abstract
Apatinib plus chemotherapy demonstrates good efficacy in multiple advanced carcinomas; however, its use in patients with advanced lung adenocarcinoma (LUAD) has not yet been assessed. The present study evaluated the potential benefits of apatinib plus chemotherapy in patients with advanced LUAD. A total of 145 patients with advanced LUAD and negative driver genes who received apatinib plus chemotherapy (n=65) or chemotherapy alone (n=80) were analyzed. The overall response rate was significantly improved by apatinib plus chemotherapy vs. chemotherapy alone (53.8 vs. 36.3%; P=0.034). Moreover, progression-free survival (PFS) was significantly longer in patients who received apatinib plus chemotherapy, compared with those who received chemotherapy alone [median (95% CI), 13.4 months (11.5-15.3) vs. 8.2 months (6.9-9.5); P<0.001], as was overall survival (OS) [median (95% CI), 23.1 months (not reached) vs. 17.0 months (14.6-19.4; P=0.001). Following adjustment by multivariate Cox regression analysis, apatinib plus chemotherapy was associated with a significantly longer PFS [hazard ratio (HR), 0.444; P<0.001] and OS (HR, 0.347; P<0.001), compared with chemotherapy alone. Subgroup analyses revealed that PFS and OS were significantly improved following apatinib plus chemotherapy vs. chemotherapy alone (all P<0.05) in patients receiving first- or second-line treatment. Notably, the incidence of hypertension was significantly increased following apatinib plus chemotherapy vs. chemotherapy alone (43.1 vs. 25.0%; P=0.021), whereas the incidence of other adverse events was not significantly different between the two treatment groups (all P>0.05). In conclusion, apatinib plus chemotherapy is associated with an improved treatment response and survival compared with chemotherapy alone, with a tolerable safety profile in patients with advanced LUAD.
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Affiliation(s)
- Hua Ye
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Wenwen Yu
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Yangyang Ni
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Xiaoqiong Bao
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Xie Zhang
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Yunlei Li
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Ali Chen
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Jifa Li
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Long Zheng
- Department of Pulmonary and Critical Care Medicine, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
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4
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Gu M, Liu Y, Xin P, Guo W, Zhao Z, Yang X, Ma R, Jiao T, Zheng W. Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches. Cancer Lett 2024; 588:216738. [PMID: 38401887 DOI: 10.1016/j.canlet.2024.216738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/08/2024] [Accepted: 02/18/2024] [Indexed: 02/26/2024]
Abstract
The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.
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Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Yang Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Peng Xin
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Zimo Zhao
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Ruiyang Ma
- Department of Otorhinolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Taiwei Jiao
- Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
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Xiong B, Bai Y, Liu J, Li T, Wang Y, Zhou C. Dual neovascular targets of vascular endothelial growth factor receptors and platelet‐derived growth factor receptor ameliorate thioacetamide induced liver fibrosis in rats. PORTAL HYPERTENSION & CIRRHOSIS 2024; 3:1-13. [DOI: 10.1002/poh2.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 01/17/2024] [Indexed: 01/05/2025]
Abstract
AbstractAimsNeovascularization plays a crucial role in liver fibrosis (LF), and blocking vascular endothelial growth factor receptors (VEGFR) has been shown to improve fibrosis. The aim of our study was to investigate the role of dual neovascularization targets, VEGFR, and platelet‐derived growth factor receptor (PDGFR), in ameliorating fibrosis.MethodsIn vitro, we observed the effects of apatinib (APA) (a VEGFR inhibitor) and donafenib (DON) (a VEGFR and PDGFR inhibitor) on the activation, proliferation, and apoptosis of hepatic stellate cells (HSCs) from rats and humans. In vivo, we established a thioacetamide (TAA)‐induced liver fibrosis rat model to explore the antifibrosis effect of APA and DON. We used the method of random table to randomly divide the rats into 4 groups. We detected the expression of angiogenesis‐related proteins using Western blot and immunohistochemistry.ResultsAPA and DON inhibited the proliferation and activation of HSCs, promoted apoptosis of HSCs, and arrested the S phase of the cell cycle in vitro. We also found that DON had a stronger inhibitory effect on HSCs. In vivo, APA and DON ameliorated liver fibrosis, reduced collagen deposition and α‐SMA expression in rats, and DON had a stronger improvement effect. APA and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/2. DON can act through both VEGF and PDGF pathways, whereas APA can only act through the VEGF pathway.ConclusionAntiangiogenesis is a promising approach for the treatment of fibrosis. Compared with a single‐target drug (APA), the dual‐target drug (DON) can achieve better therapeutic effects.
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Affiliation(s)
- Bin Xiong
- Department of Interventional Radiology The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
- Hubei Province Key Laboratory of Molecular Imaging Wuhan Hubei China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
- Hubei Province Key Laboratory of Molecular Imaging Wuhan Hubei China
| | - Tongqiang Li
- Department of Interventional Radiology The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
- Hubei Province Key Laboratory of Molecular Imaging Wuhan Hubei China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
- Hubei Province Key Laboratory of Molecular Imaging Wuhan Hubei China
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6
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Bergonzini C, Gregori A, Hagens TMS, van der Noord VE, van de Water B, Zweemer AJM, Coban B, Capula M, Mantini G, Botto A, Finamore F, Garajova I, McDonnell LA, Schmidt T, Giovannetti E, Danen EHJ. ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells. J Exp Clin Cancer Res 2024; 43:4. [PMID: 38163893 PMCID: PMC10759666 DOI: 10.1186/s13046-023-02879-8] [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: 07/14/2023] [Accepted: 10/30/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it. METHODS Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance. RESULTS Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel. CONCLUSION Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.
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Affiliation(s)
- Cecilia Bergonzini
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Alessandro Gregori
- Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
| | - Tessa M S Hagens
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Vera E van der Noord
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Bob van de Water
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Annelien J M Zweemer
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Bircan Coban
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Mjriam Capula
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Giulia Mantini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
| | - Asia Botto
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Francesco Finamore
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Liam A McDonnell
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Thomas Schmidt
- Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands.
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.
| | - Erik H J Danen
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
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Li X, Zhou J, Wang X, Li C, Ma Z, Wan Q, Peng F. New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis. Biomed Pharmacother 2023; 163:114806. [PMID: 37163782 DOI: 10.1016/j.biopha.2023.114806] [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: 02/10/2023] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/12/2023] Open
Abstract
In 1971, Folkman proposed that tumors could be limited to very small sizes by blocking angiogenesis. Angiogenesis is the generation of new blood vessels from pre-existing vessels, considered to be one of the important processes in tumor growth and metastasis. Angiogenesis is a complex process regulated by various factors and involves many secreted factors and signaling pathways. Angiogenesis is important in the transport of oxygen and nutrients to the tumor during tumor development. Therefore, inhibition of angiogenesis has become an important strategy in the clinical management of many solid tumors. Combination therapies of angiogenesis inhibitors with radiotherapy and chemotherapy are often used in clinical practice. In this article, we will review common targets against angiogenesis, the most common and up-to-date anti-angiogenic drugs and clinical treatments in recent years, including active ingredients from chemical and herbal medicines.
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Affiliation(s)
- Xin Li
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jianbo Zhou
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xue Wang
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chunxi Li
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zifan Ma
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Qiaoling Wan
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fu Peng
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
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8
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Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, Salimimoghadam S, Aref AR, Kalbasi A, Rajabi R, Rashidi M, Taheriazam A, Sethi G. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges. Pharmacol Res 2023; 187:106553. [PMID: 36400343 DOI: 10.1016/j.phrs.2022.106553] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Abbaspour
- Cellular and Molecular Research Center,Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhossein Zabolian
- Resident of department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Alireza Kalbasi
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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9
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Zhang CY, Liu S, Yang M. Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options. World J Gastroenterol 2022; 28:6827-6845. [PMID: 36632312 PMCID: PMC9827589 DOI: 10.3748/wjg.v28.i48.6827] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 11/04/2022] [Accepted: 11/28/2022] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer (PC) is the third-leading cause of cancer deaths. The overall 5-year survival rate of PC is 9%, and this rate for metastatic PC is below 3%. However, the PC-induced death cases will increase about 2-fold by 2060. Many factors such as genetic and environmental factors and metabolic diseases can drive PC development and progression. The most common type of PC in the clinic is pancreatic ductal adenocarcinoma, comprising approximately 90% of PC cases. Multiple pathogenic processes including but not limited to inflammation, fibrosis, angiogenesis, epithelial-mesenchymal transition, and proliferation of cancer stem cells are involved in the initiation and progression of PC. Early diagnosis is essential for curable therapy, for which a combined panel of serum markers is very helpful. Although some mono or combined therapies have been approved by the United States Food and Drug Administration for PC treatment, current therapies have not shown promising outcomes. Fortunately, the development of novel immunotherapies, such as oncolytic viruses-mediated treatments and chimeric antigen receptor-T cells, combined with therapies such as neoadjuvant therapy plus surgery, and advanced delivery systems of immunotherapy will improve therapeutic outcomes and combat drug resistance in PC patients. Herein, the pathogenesis, molecular signaling pathways, diagnostic markers, prognosis, and potential treatments in completed, ongoing, and recruiting clinical trials for PC were reviewed.
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Affiliation(s)
- Chun-Ye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, United States
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, United States
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Wang W, Li C, Zhuang C, Zhang H, Wang Q, Fan X, Qi M, Sun R, Yu J. Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer. Front Cardiovasc Med 2022; 9:873829. [PMID: 35811723 PMCID: PMC9262125 DOI: 10.3389/fcvm.2022.873829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Hypertension is one of the main adverse effects of antiangiogenic tumor drugs and thus limits their application. The mechanism of hypertension caused by tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors is mainly related to inhibition of the nitric oxide (NO) pathway and activation of the endothelin pathway, as well as vascular rarefaction and increased salt sensitivity; consequently, prevention and treatment differ for this type of hypertension compared with primary hypertension. Apatinib is a highly selective TKI approved in China for the treatment of advanced or metastatic gastric cancer. The RhoA/ROCK pathway is involved in the pathogenesis of hypertension and mediates smooth muscle contraction, eNOS inhibition, endothelial dysfunction and vascular remodeling. In this study, in vivo experiments were performed to explore whether the RhoA/ROCK signaling pathway is part of a possible mechanism of apatinib in the treatment of gastric cancer-induced hypertension and the impairment of vascular remodeling and left ventricular function. Y27632, a selective small inhibitor of both ROCK1 and ROCK2, was combined with apatinib, and its efficacy was evaluated, wherein it can reduce hypertension induced by apatinib treatment in gastric cancer mice and weaken the activation of the RhoA/ROCK pathway by apatinib and a high-salt diet (HSD). Furthermore, Y-27632 improved aortic remodeling, fibrosis, endothelial dysfunction, superior mesenteric artery endothelial injury, left ventricular dysfunction and cardiac fibrosis in mice by weakening the activation of the RhoA/ROCK pathway. The expression of RhoA/ROCK pathway-related proteins and relative mRNA levels in mice after apatinib intervention were analyzed by various methods, and blood pressure and cardiac function indexes were compared. Endothelial and cardiac function and collagen levels in the aorta were also measured to assess vascular and cardiac fibrosis and to provide a basis for the prevention and treatment of this type of hypertension.
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