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Xiang XS, Li PC, Wang WQ, Liu L. Histone deacetylases: A novel class of therapeutic targets for pancreatic cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188676. [PMID: 35016922 DOI: 10.1016/j.bbcan.2022.188676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is the seventh leading cause of cancer death worldwide, with a low 5-year survival rate. Novel agents are urgently necessary to treat the main pathological type, known as pancreatic ductal carcinoma (PDAC). The dysregulation of histone deacetylases (HDACs) has been identified in association with PDAC, which can be more easily targeted by small molecular inhibitors than gene mutations and may represent a therapeutic breakthrough for PDAC. However, the contributions of HDACs to PDAC remain controversial, and pharmacokinetic challenges have limited the application of HDAC inhibitors (HDACis) in PDAC. This review summarizes the mechanisms associated with success and failure of HDACis in PDAC and discusses the recent progress made in HDACi development and application, such as combination therapies designed to enhance efficacy. More precise strategies involving HDACis might eventually improve the outcomes of PDAC treatment.
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Affiliation(s)
- Xue-Song Xiang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng-Cheng Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Zhang L, Wu M, Su R, Zhang D, Yang G. The efficacy and mechanism of proteasome inhibitors in solid tumor treatment. Recent Pat Anticancer Drug Discov 2021; 17:268-283. [PMID: 34856915 DOI: 10.2174/1574892816666211202154536] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. OBJECTIVE This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. METHODS We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. RESULTS/CONCLUSION Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition-associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-κB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors' anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.
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Affiliation(s)
- Lei Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118. China
| | - Mengyang Wu
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118. China
| | - Ruicong Su
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118. China
| | - Di Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118. China
| | - Guilian Yang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118. China
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Arpalahti L, Haglund C, Holmberg CI. Proteostasis Dysregulation in Pancreatic Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:101-115. [PMID: 32274754 DOI: 10.1007/978-3-030-38266-7_4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), has a dismal 5-year survival rate of less than 5%. Radical surgical resection, in combination with adjuvant chemotherapy, provides the best option for long-term patient survival. However, only approximately 20% of patients are resectable at the time of diagnosis, due to locally advanced or metastatic disease. There is an urgent need for the identification of new, specific, and more sensitive biomarkers for diagnosis, prognosis, and prediction to improve the treatment options for pancreatic cancer patients. Dysregulation of proteostasis is linked to many pathophysiological conditions, including various types of cancer. In this review, we report on findings relating to the main cellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, in pancreatic cancer. The expression of several components of the proteolytic network, including E3 ubiquitin-ligases and deubiquitinating enzymes, are dysregulated in PDAC, which accounts for approximately 90% of all pancreatic malignancies. In the future, a deeper understanding of the emerging role of proteostasis in pancreatic cancer has the potential to provide clinically relevant biomarkers and new strategies for combinatorial therapeutic options to better help treat the patients.
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Affiliation(s)
- Leena Arpalahti
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- Research Programs Unit, Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Carina I Holmberg
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.
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Park JK, Kim Y, Kim H, Jeon J, Kim TW, Park JH, Hwnag YI, Lee WJ, Kang JS. The anti-fibrotic effect of GV1001 combined with gemcitabine on treatment of pancreatic ductal adenocarcinoma. Oncotarget 2018; 7:75081-75093. [PMID: 27655706 PMCID: PMC5342724 DOI: 10.18632/oncotarget.12057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 08/23/2016] [Indexed: 02/07/2023] Open
Abstract
GV1001 is a telomerase-based cancer vaccine made of a 16-mer telomerase reverse transcriptase (TERT) peptide, and human TERT, the rate-limiting subunit of the telomerase complex, is an attractive target for cancer vaccination. The aim of this study was to evaluate the effect of telomerase peptide vaccination, GV1001 combined with gemcitabine in treatment of pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines were used in vitro experiment and also, PDAC xenograft mice model was established using PANC1, AsPC1 and CD133+ AsPC1 (PDAC stem cell). Treatment groups were divided as follows; control, gemcitabine, GV1001, gemcitabine and GV1001 combination. The inflammatory cytokines were measured from the blood, and xenograft tumor specimens were evaluated. GV1001 treatment alone did not affect the proliferation or the apoptosis of PDAC cells. Gemcitabine alone and gemcitabine with GV1001 groups had significantly reduced in tumor size and showed abundant apoptosis compared to other treatment groups. Surprisingly, xenograft PDAC tumor specimens of gemcitabine alone group had been replaced by severe fibrosis whereas gemcitabine with GV1001 group had significantly less fibrosis. Blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β increased in gemcitabine alone group, however, it was decreased in gemcitabine with GV1001 group. GV1001 combined with gemcitabine treatment showed significant loss of fibrosis in tumor tissue as well as tumor cell death. Therefore, further investigation of GV1001 effect combined with gemcitabine treatment may give us useful insights to overcome the hurdle in anti-cancer drug delivery over massive fibrosis around PDACs.
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Affiliation(s)
- Joo Kyung Park
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yejin Kim
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyemin Kim
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Jane Jeon
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Wan Kim
- Department of Ophthalmology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ji-Hong Park
- Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do, Korea
| | - Young-Il Hwnag
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Wang Jae Lee
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Seung Kang
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
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Huang W, Yuan X, Sun T, Fan S, Wang J, Zhou Q, Guo W, Ran F, Ge Z, Yang H, Li R, Cui J. Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells. Front Pharmacol 2017; 8:476. [PMID: 28883791 PMCID: PMC5574410 DOI: 10.3389/fphar.2017.00476] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 07/03/2017] [Indexed: 12/20/2022] Open
Abstract
Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.
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Affiliation(s)
- Wei Huang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical CollegeBeijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Xia Yuan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Ting Sun
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Shujie Fan
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical CollegeBeijing, China
| | - Jun Wang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical CollegeBeijing, China
| | - Quan Zhou
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Wei Guo
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Fuxiang Ran
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Zemei Ge
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Runtao Li
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
| | - Jingrong Cui
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing, China
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Klieser E, Swierczynski S, Mayr C, Schmidt J, Neureiter D, Kiesslich T, Illig R. Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy. World J Gastrointest Oncol 2015; 7:473-483. [PMID: 26691388 PMCID: PMC4678394 DOI: 10.4251/wjgo.v7.i12.473] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/03/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.
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Seicean A, Petrusel L, Seicean R. New targeted therapies in pancreatic cancer. World J Gastroenterol 2015; 21:6127-6145. [PMID: 26034349 PMCID: PMC4445091 DOI: 10.3748/wjg.v21.i20.6127] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 02/26/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023] Open
Abstract
Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.
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Liu DL, Bu HQ, Jin HM, Zhao JF, Li Y, Huang H. Enhancement of the effects of gemcitabine against pancreatic cancer by oridonin via the mitochondrial caspase-dependent signaling pathway. Mol Med Rep 2014; 10:3027-34. [PMID: 25242370 DOI: 10.3892/mmr.2014.2584] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 07/27/2014] [Indexed: 11/06/2022] Open
Abstract
Gemcitabine is a first‑line chemotherapeutic agent used in the treatment of pancreatic cancer; however resistance of the disease to the drug often develops over time. Agents that can either enhance the effects of gemcitabine, or help to overcome the chemoresistance to the drug are needed for the successful treatment of pancreatic cancer. Oridonin is one such agent which is safe and multi‑targeted and has previously been shown to induce apoptosis in other tumor cells, through mitochondrial signaling pathways. The aims of the present study were to evaluate whether oridonin may enhance the effects of gemcitabine on pancreatic cancer in vitro and to investigate the possible mechanisms of this enhancement. In vitro studies have previously shown that oridonin can inhibit the proliferation of the Panc‑1 pancreatic cancer cell line, and potentiate gemcitabine‑induced apoptosis, which was shown to be associated with cell cycle arrest in the G1 phase. Western blot and quantitative polymerase chain reaction analyses demonstrated that the expression levels of the anti‑apoptotic gene Bcl‑2 and the Bcl‑2/Bax ratio in the oridonin and the oridonin plus gemcitabine groups were significantly downregulated as compared with the gemcitabine treatment and control groups. The expression levels of pro‑apoptotic genes Bax, cytochrome c (cyt c), and caspase‑3 and ‑9 in the oridonin and the combination groups were significantly upregulated as compared with the other two groups. The results suggested that oridonin improved the anti‑tumor effects of gemcitabine through the enhancement of gemcitabine‑induced apoptosis.This mechanism may be through the downregulation of Bcl‑2 expression and the upregulation of Bax expression, resulting in the reduction of the Bcl‑2/Bax ratio. These effects may promote the release of cyt c from the mitochondria into the cytoplasm thus triggering the mitochondrial apoptosis signaling pathway. Furthermore, caspase‑3 and ‑9 were shown to be activated as a result of the induction of apoptosis.
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Affiliation(s)
- Dian-Lei Liu
- Department of General Surgery, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
| | - He-Qi Bu
- Department of Anorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
| | - Hai-Min Jin
- Department of General Surgery, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
| | - Jin-Feng Zhao
- Department of General Surgery, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
| | - Ye Li
- Department of General Surgery, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
| | - Hai Huang
- Department of General Surgery, Guangxing Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
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Paik WH, Ryu JK, Jeong KS, Park JM, Song BJ, Lee SH, Kim YT, Yoon YB. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer. World J Gastroenterol 2014; 20:8545-8557. [PMID: 25024609 PMCID: PMC4093704 DOI: 10.3748/wjg.v20.i26.8545] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 02/27/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line.
METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed.
RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse.
CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process.
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Huang C, Du J, Xie K. FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta Rev Cancer 2014; 1845:104-16. [PMID: 24418574 DOI: 10.1016/j.bbcan.2014.01.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 12/30/2013] [Accepted: 01/03/2014] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is a devastating disease with an overall 5-year survival rate less than 5%. Multiple signaling pathways are implicated in the pathogenesis of pancreatic cancer, such as Wnt/β-catenin, Notch, Hedgehog, hypoxia-inducible factor, signal transducer and activator of transcription, specificity proteins/Krüppel-like factors, and Forkhead box (FOX). Recently, increasing evidence has demonstrated that the transcription factor FOXM1 plays important roles in the initiation, progression, and metastasis of a variety of human tumors, including pancreatic cancer. In this review, we focus on the current understanding of the molecular pathogenesis of pancreatic cancer with a special focus on the function and regulation of FOXM1 and rationale for FOXM1 as a novel molecular target for pancreatic cancer prevention and treatment.
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Affiliation(s)
- Chen Huang
- Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China; Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Jiawei Du
- Department of Laboratory Medicine, Zhenjiang Second People's Hospital, Jiangsu University College of Medicine, Zhenjiang, People's Republic of China
| | - Keping Xie
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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van Kampen JGM, Marijnissen-van Zanten MAJ, Simmer F, van der Graaf WTA, Ligtenberg MJL, Nagtegaal ID. Epigenetic targeting in pancreatic cancer. Cancer Treat Rev 2014; 40:656-64. [PMID: 24433955 DOI: 10.1016/j.ctrv.2013.12.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/18/2013] [Accepted: 12/21/2013] [Indexed: 12/22/2022]
Abstract
The prognosis of pancreatic cancer patients is very poor, with a 5-year survival of less than 6%. Therefore, there is an urgent need for new therapeutic options in pancreatic cancer. In the past years it became evident that deregulation of epigenetic mechanisms plays an important role in pancreatic carcinogenesis. This review focuses on the exploitation of drugs that alter histone modifications, DNA methylation and microRNA expression as options for the treatment of pancreatic cancer.
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Affiliation(s)
- Jasmijn G M van Kampen
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Urology 267, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | | | - Femke Simmer
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Winette T A van der Graaf
- Department of Medical Oncology 452, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Marjolijn J L Ligtenberg
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Human Genetics 855, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Iris D Nagtegaal
- Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Tran K, Risingsong R, Royce DB, Williams CR, Sporn MB, Pioli PA, Gediya LK, Njar VC, Liby KT. The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer. Carcinogenesis 2012; 34:199-210. [PMID: 23042302 DOI: 10.1093/carcin/bgs319] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Novel drugs and drug combinations are needed for the chemoprevention and treatment of cancer. We show that the histone deacetylase inhibitor vorinostat [suberoylanilide hydroxamic acid (SAHA)] and the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me and CDDO-Ea, respectively) cooperated to inhibit the de novo synthesis of nitric oxide in RAW 264.7 macrophage-like cells and in primary mouse peritoneal macrophages. Additionally, SAHA enhanced the ability of synthetic triterpenoids to delay formation of estrogen receptor-negative mammary tumors in MMTV-polyoma middle T (PyMT) mice. CDDO-Me (50 mg/kg diet) and SAHA (250 mg/kg diet) each significantly delayed the initial development of tumors by 4 (P < 0.001) and 2 (P < 0.05) weeks, respectively, compared with the control group in the time required to reach 50% tumor incidence. CDDO-Ea (400 mg/kg diet), as a single agent, did not delay tumor development. The combination of either triterpenoid with SAHA was significantly more potent than the individual drugs for delaying tumor development, with a 7 week (P < 0.001) delay before 50% tumor incidence was reached. SAHA, alone and in combination with CDDO-Me, also significantly (P < 0.05) inhibited the infiltration of tumor-associated macrophages into the mammary glands of PyMT mice and levels of the chemokine macrophage colony-stimulating factor in primary PyMT tumor cells. In addition, SAHA and the synthetic triterpenoids cooperated to suppress secreted levels of the pro-angiogenic factor matrix metalloproteinase-9. Similar results were observed in mouse models of pancreatic and lung cancer. At concentrations that were anti-inflammatory, SAHA had no effect on histone acetylation. These studies suggest that both SAHA and triterpenoids effectively delay tumorigenesis, thereby demonstrating a promising, novel drug combination for chemoprevention.
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Affiliation(s)
- Kim Tran
- Department of Pharmacology or Medicine, Dartmouth Medical School, Hanover, NH 03755, USA
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