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1
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Gu D, Huang S, Zhao K, Zhang X, Zhang J, Xiong W. Global trends in resistance studies of gemcitabine and pancreatic cancer: a bibliometric and visual analysis from 2010 to 2024. Front Pharmacol 2025; 16:1564561. [PMID: 40351434 PMCID: PMC12062017 DOI: 10.3389/fphar.2025.1564561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/31/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Pancreatic adenocarcinoma (PC) represents a prevalent and highly aggressive malignancy within the digestive system, characterized by an exceedingly poor prognosis and a dismal 5-year survival rate of below 7%. Gemcitabine (GEM) remains the cornerstone chemotherapeutic agent in the management of PC; however, the growing challenge of GEM chemoresistance, which undermines treatment efficacy, represents a significant obstacle in clinical practice. To date, no comprehensive bibliometric analysis has been undertaken to systematically explore studies on GEM resistance in the context of PC. This study aims to deliver a thorough evaluation of the research hotspots pertaining to GEM resistance in PCs. Method A systematic search was conducted for articles published from 1 January 2010, to 15 December 2024, focusing on resistance studies of GEM in PC. Bibliometric analysis and visualization were performed utilizing VOSviewer and CiteSpace tools, applied to literature data extracted from the Web of Science Core Collection (WoSCC). Results Between 2010 and 2024, a total of 2,689 papers were published across 472 institutions in 74 countries, reflecting a consistent upward trajectory in annual publication output. China and Fudan University emerged as the leading contributors to the research output on this topic, representing the most prolific country and institution, respectively. Giovannetti, Elisa, and Yu, Xianjun are the most prolific scholars in this field. Cancer Research stands out as the most cited and impactful journal, while research on the tumor microenvironment, targeted therapy, and circular RNA has emerged as a key focus area in recent years. Conclusion This study provides a systematic and comprehensive overview of the literature on GEM resistance in PC over the past 15 years. This analysis offers scholars critical insights into the field from a bibliometric perspective, potentially informing future studies on the development of chemotherapeutic treatments for PC.
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Affiliation(s)
- Dandan Gu
- Department of Gastroenterology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Shaoyang Huang
- College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Kai Zhao
- Department of Gastroenterology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Xiaohong Zhang
- Department of Gastroenterology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Jinjing Zhang
- Department of Gastroenterology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Wei Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Testing in Universities of Yunnan Province, School of Basic Medical Sciences, Dali University, Dali, China
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2
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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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3
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Daya T, Breytenbach A, Gu L, Kaur M. Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159578. [PMID: 39542394 DOI: 10.1016/j.bbalip.2024.159578] [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: 07/24/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024]
Abstract
Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.
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Affiliation(s)
- Tasvi Daya
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Andrea Breytenbach
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Liang Gu
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa.
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4
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Nguyen H, Luong NH, Peil JK, Tong Y, Mitchell DK, Fishel ML, Lin CC. Fast-Relaxing Hydrogels Promote Pancreatic Adenocarcinoma Cell Aggressiveness through Integrin β1 Signaling. Biomacromolecules 2025; 26:1098-1110. [PMID: 39841789 PMCID: PMC11817685 DOI: 10.1021/acs.biomac.4c01441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) exhibiting high stiffness and fast stress relaxation. In this work, gelatin-based viscoelastic hydrogels were developed to mimic the compositions, stiffness, and fast stress relaxation of PDAC tissues. The hydrogels were cross-linked by gelatin-norbornene-boronic acid (GelNB-BA), thiolated macromers, and a 1,2-diol-containing linear synthetic polymer PHD. Controlling the thiol-norbornene cross-linking afforded tunable stiffness, whereas increasing PHD content led to hydrogels with PDAC-mimicking fast stress relaxation. In vitro studies, including proliferation, morphology, and mRNA-sequencing, showed that fast-relaxing hydrogels supported PDAC cell proliferation, epithelial-mesenchymal transition (EMT), and integrin β1 activation. Blocking integrin β1 in vitro led to upregulating EMT markers in both slow and fast-relaxing hydrogels. However, this strategy profoundly impacted tumor growth rate and reduced tumor size but did not alter metastasis patterns in an orthotopic mouse model. This suggests a need to further evaluate the antitumor effect of integrin β1 blockade.
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Affiliation(s)
- Han Nguyen
- Weldon
School of Biomedical Engineering, Purdue
University, West Lafayette, Indiana 47907, United States
| | - Ngoc Ha Luong
- Weldon
School of Biomedical Engineering, Purdue
University, West Lafayette, Indiana 47907, United States
| | - Jacqueline K. Peil
- Department
of Pediatrics, Indiana University School
of Medicine, Indianapolis, Indiana 46202, United States
| | - Yan Tong
- Department
of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana
University Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
| | - Dana K. Mitchell
- Department
of Pediatrics, Indiana University School
of Medicine, Indianapolis, Indiana 46202, United States
| | - Melissa L. Fishel
- Department
of Pediatrics, Indiana University School
of Medicine, Indianapolis, Indiana 46202, United States
- Department
of Pharmacology and Toxicology, Indiana
University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana
University Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
| | - Chien-Chi Lin
- Weldon
School of Biomedical Engineering, Purdue
University, West Lafayette, Indiana 47907, United States
- Indiana
University Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
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5
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Allen D, Szoo MJ, van Bergen TD, Seppelin A, Oh J, Saad MA. Near-infrared photoimmunotherapy: mechanisms, applications, and future perspectives in cancer research. Antib Ther 2025; 8:68-85. [PMID: 39958565 PMCID: PMC11826922 DOI: 10.1093/abt/tbaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/01/2024] [Accepted: 01/16/2025] [Indexed: 02/18/2025] Open
Abstract
Photoimmunotherapy (PIT) involves the targeted delivery of a photosensitizer through antibody conjugation, which, upon binding to its cellular target and activation by external irradiation, induces localized toxicity. This approach addresses several limitations of conventional cancer therapies, such as chemo- and radiotherapies, which result in off-target effects that significantly reduce patient quality of life. Furthermore, PIT improves on the challenges encountered with photodynamic therapy (PDT), such as nonspecific localization of the photosensitizer, which often results in unintended toxicities. Although PIT was first proposed in the early 1980s, its clinical applications have been constrained by limitations in antibody engineering, conjugation chemistries, and optical technologies. However, recent advances in antibody-drug conjugate (ADC) research and the emergence of sophisticated laser technologies have greatly benefited the broader applicability of PIT. Notably, the first near-infrared photoimmunotherapy (NIR-PIT) treatment for head and neck cancer has been approved in Japan and is currently in phase III clinical trials in the USA. A significant advantage of PIT over traditional ADCs in cancer management is the agnostic nature of PDT, making it more adaptable to different tumor types. Specifically, PIT can act on cancer stem cells and cancer cells displaying treatment resistance and aggressive phenotypes-a capability beyond the scope of ADCs alone. This review provides an overview of the mechanism of action of NIR-PIT, highlighting its adaptability and application in cancer therapeutics, and concludes by exploring the potential of PIT in advancing cancer treatments.
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Affiliation(s)
- Derek Allen
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - Madeline JoAnna Szoo
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
- Department of Biochemistry, Northeastern University, Boston, MA 02115, United States
| | - Tessa D van Bergen
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - Ani Seppelin
- Department of Biochemistry, Northeastern University, Boston, MA 02115, United States
| | - Jeonghyun Oh
- Department of Physics, Northeastern University, Boston, MA 02115, United States
| | - Mohammad A Saad
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
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6
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Pino MTL, Rocca MV, Acosta LH, Cabilla JP. Challenging the Norm: The Unrecognized Impact of Soluble Guanylyl Cyclase Subunits in Cancer. Int J Mol Sci 2024; 25:10053. [PMID: 39337539 PMCID: PMC11432225 DOI: 10.3390/ijms251810053] [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: 06/19/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/30/2024] Open
Abstract
Since the discovery of nitric oxide (NO), a long journey has led us to the present, during which much knowledge has been gained about its pathway members and their roles in physiological and various pathophysiological conditions. Soluble guanylyl cyclase (sGC), the main NO receptor composed of the sGCα1 and sGCβ1 subunits, has been one of the central figures in this narrative. However, the sGCα1 and sGCβ1 subunits remained obscured by the focus on sGC's enzymatic activity for many years. In this review, we restore the significance of the sGCα1 and sGCβ1 subunits by compiling and analyzing available but previously overlooked information regarding their roles beyond enzymatic activity. We delve into the basics of sGC expression regulation, from its transcriptional regulation to its interaction with proteins, placing particular emphasis on evidence thus far demonstrating the actions of each sGC subunit in different tumor models. Exploring the roles of sGC subunits in cancer offers a valuable opportunity to enhance our understanding of tumor biology and discover new therapeutic avenues.
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Affiliation(s)
- María Teresa L Pino
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - María Victoria Rocca
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - Lucas H Acosta
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - Jimena P Cabilla
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
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7
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Zhu Y, Xing X, Wang F, Chen L, Zhong C, Lu X, Yu Z, Yang Y, Yao Y, Song Q, Han S, Liu Z, Zhang P. The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport. FEBS Lett 2024; 598:1967-1980. [PMID: 38886124 DOI: 10.1002/1873-3468.14955] [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: 02/16/2024] [Revised: 04/25/2024] [Accepted: 05/27/2024] [Indexed: 06/20/2024]
Abstract
The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy.
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Affiliation(s)
- Yue Zhu
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, China
- Cancer Center, Renmin Hospital of Wuhan University, China
| | - Xiaoke Xing
- Cancer Center, Renmin Hospital of Wuhan University, China
| | - Fuxing Wang
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
| | - Luojun Chen
- Cancer Center, Renmin Hospital of Wuhan University, China
| | - Chunhui Zhong
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
| | - Xiting Lu
- School of Applied Biology, Shenzhen Institute of Technology, China
| | - Zhanwang Yu
- School of Applied Biology, Shenzhen Institute of Technology, China
| | - Yongbo Yang
- School of Life Sciences, Central China Normal University, Wuhan, China
| | - Yi Yao
- Cancer Center, Renmin Hospital of Wuhan University, China
| | - Qibin Song
- Cancer Center, Renmin Hospital of Wuhan University, China
| | - Suxia Han
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Zheng Liu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China
| | - Pingfeng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, China
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8
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Gancedo SN, Sahores A, Gómez N, Di Siervi N, May M, Yaneff A, de Sousa Serro MG, Fraunhoffer N, Dusetti N, Iovanna J, Shayo C, Davio CA, González B. The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer. Front Pharmacol 2024; 15:1432851. [PMID: 39114357 PMCID: PMC11303182 DOI: 10.3389/fphar.2024.1432851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
The xenobiotic transporter ABCC4/MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with a more aggressive phenotype and metastatic propensity. Here, we show that ABCC4 promotes epithelial-mesenchymal transition (EMT) in PDAC, a hallmark process involving the acquisition of mesenchymal traits by epithelial cells, enhanced cell motility, and chemoresistance. Modulation of ABCC4 levels in PANC-1 and BxPC-3 cell lines resulted in the dysregulation of genes present in the EMT signature. Bioinformatic analysis on several cohorts including tumor samples, primary patient-derived cultured cells, patient-derived xenografts, and cell lines, revealed a positive correlation between ABCC4 expression and EMT markers. We also characterized the ABCC4 cistrome and identified four candidate clusters in the distal promoter and intron one that showed differential binding of pro-epithelial FOXA1 and pro-mesenchymal GATA2 transcription factors in low ABCC4-expressing HPAF-II and high ABCC4-expressing PANC-1 xenografts. HPAF-II xenografts showed exclusive binding of FOXA1, and PANC-1 xenografts exclusive binding of GATA2, at ABCC4 clusters, consistent with their low and high EMT phenotype respectively. Our results underscore ABCC4/MRP4 as a valuable prognostic marker and a potential therapeutic target to treat PDAC subtypes with prominent EMT features, such as the basal-like/squamous subtype, characterized by worse prognosis and no effective therapies.
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Affiliation(s)
- S. N. Gancedo
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - A. Sahores
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - N. Gómez
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - N. Di Siervi
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - M. May
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - A. Yaneff
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - M. G. de Sousa Serro
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - N. Fraunhoffer
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
| | - N. Dusetti
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
| | - J. Iovanna
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
- Hospital de Alta Complejidad El Cruce, Argentina. Universidad Nacional Arturo Jauretche, Buenos Aires, Argentina
| | - C. Shayo
- Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
| | - C. A. Davio
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - B. González
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
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9
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Huang Y, Xue C, Bu R, Wu C, Li J, Zhang J, Chen J, Shi Z, Chen Y, Wang Y, Liu Z. Inhibition and transport mechanisms of the ABC transporter hMRP5. Nat Commun 2024; 15:4811. [PMID: 38844452 PMCID: PMC11156954 DOI: 10.1038/s41467-024-49204-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 05/24/2024] [Indexed: 06/09/2024] Open
Abstract
Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.
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Affiliation(s)
- Ying Huang
- Shenzhen Key Labortory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Chenyang Xue
- Shenzhen Key Labortory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Ruiqian Bu
- Shenzhen Key Labortory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Cang Wu
- Shenzhen Key Labortory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Jiachen Li
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China
| | - Jinqiu Zhang
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China
| | - Jinyu Chen
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China
| | - Zhaoying Shi
- Department Of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Yonglong Chen
- Department Of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Yong Wang
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China.
- The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, 314400, China.
| | - Zhongmin Liu
- Shenzhen Key Labortory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
- Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
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10
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Singh S. Review on Natural Agents as Aromatase Inhibitors: Management of Breast Cancer. Comb Chem High Throughput Screen 2024; 27:2623-2638. [PMID: 37861041 DOI: 10.2174/0113862073269599231009115338] [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: 06/28/2023] [Revised: 08/16/2023] [Accepted: 09/21/2023] [Indexed: 10/21/2023]
Abstract
Breast cancer is a prevalent type of cancer that is typically hormone-dependent, caused by estrogen. Aromatase inhibitors are frequently utilised in the treatment of hormonereceptor- positive breast cancer because they prevent the enzyme aromatase from converting androgens to estrogens. Natural medicines with aromatase inhibitory characteristics have attracted interest as potential alternatives or complementary therapy to manufactured medications. This review discusses the function of natural agents as aromatase inhibitors in treating breast cancer. A variety of natural compounds have been investigated for their capacity to inhibit aromatase activity and lower estrogen levels. These agents include resveratrol from red wine and grapes, curcumin from turmeric extract and green teahigh in catechins, and other flavonoids such as genistein, luteolin and quercetin. It has been demonstrated that by decreasing estrogen synthesis, they can slow the growth of breast cancer cells that are dependent on estrogen. However, the clinical evidence supporting their efficacy and safety in breast cancer treatment is inadequate. More research is required to investigate the therapeutic potential of natural medicines, such as aromatase inhibitors, in treating breast cancer. The clinical trials are required to assess their efficacy, appropriate doses, and potential interactions with other therapies. In conclusion, natural aromatase inhibitory drugs are promising adjuncts in the treatment of hormone receptor-positive breast cancer. Their clinical value and safety profile, however, require additional investigation.
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Affiliation(s)
- Sonia Singh
- Institute of Pharmaceutical Research, GLA University Mathura, U.P: 281406, India
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11
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Zihlif M, Hameduh T, Bulatova N, Hammad H. Alteration in the expression of the chemotherapy resistance‑related genes in response to chronic and acute hypoxia in pancreatic cancer. Biomed Rep 2023; 19:88. [PMID: 37901880 PMCID: PMC10603373 DOI: 10.3892/br.2023.1670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 09/08/2023] [Indexed: 10/31/2023] Open
Abstract
Pancreatic cancer is currently one of the least curable types of human cancer and remains a key health problem. One of the most important characteristics of pancreatic cancer is its ability to grow under hypoxic conditions. Hypoxia is associated with resistance of cancer cells to radiotherapy and chemotherapy. It is a major contributor to pancreatic cancer genetic instability, which local and systemic resistance that may result in poor clinical outcome. Accordingly, identifying gene expression changes in cancer resistance genes that occur under hypoxic conditions may identify a new therapeutic target. The aim of the present study was to explore the association between hypoxia and resistance to chemotherapy and determine the alteration in the expression of cancer resistance-related genes in the presence of hypoxia. Pancreatic cancer cells (PANC-1) were exposed to 8 h hypoxic episodes (<1% oxygen) three times/week for a total of 20 episodes (chronic hypoxia) or 72 h hypoxic episodes twice/week for a total of 10 episodes (acute hypoxia). The alterations in gene expression were examined using reverse transcription-quantitative PCR array compared with normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay. Both chronic and acute hypoxia induced chemoresistance toward doxorubicin in PANC-1 pancreatic cancer cell line. The greatest changes occurred in estrogen Receptor Alpha Gene (ESR1) and ETS Like-1 protein (ELK1) pathways, in nucleic transcription factor Peroxisome proliferator-activated receptors (PPARs) and in a cell cycle inhibitor cyclin dependent kinase inhibitor 1A (CDKN1A). The present study demonstrated that exposing cells to prolonged hypoxia results in different gene expression changes involving pleotropic pathways that serve a role in inducing resistance in pancreatic cancer.
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Affiliation(s)
- Malek Zihlif
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Tareq Hameduh
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Nailya Bulatova
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Hana Hammad
- Department of Biology, School of Science, The University of Jordan, Amman 11942, Jordan
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12
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Land G, Van Haeringen B, Cooper C, Andelkovic V, O'Rourke T. A Rare Case of Rhabdoid Pancreatic Carcinoma: Prolonged Disease-Free Survival Following Upfront Resection and Adjuvant Chemotherapy. Cureus 2023; 15:e50145. [PMID: 38186431 PMCID: PMC10771581 DOI: 10.7759/cureus.50145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
The rhabdoid subtype of undifferentiated pancreatic carcinoma is rarely reported. The clinical course of this disease is therefore poorly understood, although it is apparently an aggressive malignancy. We herein discuss the case of a 69-year-old man presenting with a rapidly enlarging mass of the pancreatic body and tail who was diagnosed with locally advanced SMARCB1-deficient undifferentiated pancreatic carcinoma with rhabdoid features, treated with radical resection and adjuvant chemotherapy, and has achieved 18-month disease-free survival ongoing at the time of article publication. We identify and contrast our case with 15 similar tumors reported in the English literature, briefly discuss the biology of this tumor, its relationship to malignant rhabdoid tumors of childhood, the role of SMARCB1 and its parent complex switch/sucrose-non-fermentable chromatin remodeling complex (SWI/SNF) in modulating the behavior of pancreatic malignancy, and the potential therapeutic avenues available for SWI/SNF-mutated malignancies.
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Affiliation(s)
- Gabriel Land
- General Surgery, Princess Alexandra Hospital, Brisbane, AUS
| | | | - Caroline Cooper
- Anatomical Pathology, Princess Alexandra Hospital, Brisbane, AUS
| | | | - Thomas O'Rourke
- Hepatobiliary Surgery, Princess Alexandra Hospital, Brisbane, AUS
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13
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Zhou X, Mitra R, Hou F, Zhou S, Wang L, Jiang W. Genomic Landscape and Potential Regulation of RNA Editing in Drug Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207357. [PMID: 36912579 PMCID: PMC10190536 DOI: 10.1002/advs.202207357] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/31/2023] [Indexed: 05/18/2023]
Abstract
Adenosine-to-inosine RNA editing critically affects the response of cancer therapies. However, comprehensive identification of drug resistance-related RNA editing events and systematic understanding of how RNA editing mediates anticancer drug resistance remain unclear. Here, 7157 differential editing sites (DESs) are identified from 98 127 informative RNA editing sites in tumor tissues, many of which are validated in cancer cell lines. Diverse editing patterns of DESs are discovered in resistant samples, which could not be fully explained by adenosine deaminase acting on RNA enzymes. Some RNA-binding proteins are identified that potentially regulate these editing events. Notably, the DESs are significantly enriched in 3'-untranslated regions (3'-UTRs). The impact of DESs in 3'-UTR on the microRNA (miRNA) regulations is explored, and some triplets (DES, miRNA, and gene) that may contribute to drug resistance are identified. In addition, it is determined that the functions of genes enriched with DESs are associated with drug resistance, such as apoptosis, drug metabolism, and DNA synthesis involved in DNA repair. An online resource (http://www.jianglab.cn/REDR/) to support convenient retrieval of DESs is also built. The findings reveal the landscape and potential regulatory mechanism of RNA editing in drug resistance, providing new therapeutic targets for reversing drug resistance.
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Affiliation(s)
- Xu Zhou
- Department of Biomedical EngineeringNanjing University of Aeronautics and AstronauticsNanjing211106P. R. China
| | - Ramkrishna Mitra
- Department of PharmacologyPhysiology, and Cancer BiologySidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvania19107USA
| | - Fei Hou
- Department of Biomedical EngineeringNanjing University of Aeronautics and AstronauticsNanjing211106P. R. China
| | - Shunheng Zhou
- Department of Biomedical EngineeringNanjing University of Aeronautics and AstronauticsNanjing211106P. R. China
| | - Lihong Wang
- Department of PathophysiologySchool of MedicineSoutheast UniversityNanjing210009P. R. China
| | - Wei Jiang
- Department of Biomedical EngineeringNanjing University of Aeronautics and AstronauticsNanjing211106P. R. China
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14
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Ding X, Zhang Y, Liang J, Yin J, Akbar N, Miguel V, Zhou Y. The long non-coding RNA CRNDE promotes osteosarcoma proliferation and migration by sponging miR-136-5p/MRP9 axis. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:835. [PMID: 36034978 PMCID: PMC9403929 DOI: 10.21037/atm-22-3602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/29/2022] [Indexed: 01/17/2023]
Abstract
Background The long-noncoding RNA colorectal neoplasia differentially expressed (CRNDE) gene has been found to be upregulated in several solid tumors. Whether CRNDE affects osteosarcoma (OS) and its underling mechanism remains unknown. Methods Tumor tissues and corresponding normal tissues were collected from 45 patients with OS. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied to determine lncRNA CRNDE level in the tissues. Participants were divided into a high CRNDE group and a low CRNDE group according to the median value of lncRNA CRNDE expression detected by in situ hybridization (ISH). The differences between high and low expression of lncRNA CRNDE in patients were compared clinically by chi-square test. Kaplan-Meier survival analysis was applied to analyze the relationship between lncRNA CRNDE expression and patient survival. Subsequently, silencing or overexpression of lncRNA CRNDE were performed in MG63 and 143B cell lines, qRT-PCR was applied to verify the expression of lncRNA CRNDE, miR-136-5p, and MRP9; dual-luciferase reporter assay was used to evaluate the targeting relationship between miR-136-5p, lncRNA CRNDE, and Cell Counting Kit-8 (CCK8), wound-healing, and Transwell assays were used to analyze for cell proliferation, migration, and invasion, respectively, and western blot was used to detect expression in cells. Results The expression of CRNDE in OS tissues was higher than that in normal tissues. High lncRNA CRNDE expression was significantly associated with clinical stage, lung metastasis, and poor prognosis in OS patients. Additionally, overexpression of lncRNA CRNDE promoted proliferation and migration of OS cells. Bioinformatics analysis showed that lncRNA CRNDE competitively inhibited miR-136-5p through acting as a competitive endogenous RNA (ceRNA). It was also revealed that miR-136-5p is a binding target gene of lncRNA CRNDE and that MRP9 is involved in this process as a downstream target gene of miR-136-5p. Conclusions The lncRNA CRNDE promotes the proliferation and migration of OS cells by regulating the miR-136-5p/MRP9 pathway, and lncRNA CRNDE can be a significant marker of OS prognosis.
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Affiliation(s)
- Xiaomin Ding
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yawen Zhang
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinrong Liang
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Junyi Yin
- Department of Medical Oncology, Shanghai Tongji University Affiliated Tongji Hospital, Shanghai, China
| | - Naveed Akbar
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Verónica Miguel
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Hospital, Aachen, Germany
| | - Yan Zhou
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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15
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Marin JJG, Monte MJ, Macias RIR, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Cives-Losada C, Di Giacomo S, Gonzalez-Gallego J, Mauriz JL, Efferth T, Briz O. Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers. Cancers (Basel) 2022; 14:cancers14143524. [PMID: 35884584 PMCID: PMC9320734 DOI: 10.3390/cancers14143524] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary One-third of the approximately 10 million deaths yearly caused by cancer worldwide are due to hepatobiliary, pancreatic, and gastrointestinal tumors. One primary reason for this high mortality is the lack of response of these cancers to pharmacological treatment. More than 100 genes have been identified as responsible for seven mechanisms of chemoresistance, but only a few of them play a critical role. These include ABC proteins (mainly MDR1, MRP1-6, and BCRP), whose expression pattern greatly determines the individual sensitivity of each tumor to pharmacotherapy. Abstract Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.
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Affiliation(s)
- Jose J. G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Rocio I. R. Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
| | - Silvia Di Giacomo
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy;
| | - Javier Gonzalez-Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Jose L. Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany;
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
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Kong L, Du J, Gu J, Deng J, Guo Y, Tao B, Jin C, Fu D, Li J. Gemcitabine-Loaded Albumin Nanoparticle Exerts An Antitumor Effect on Gemcitabine-Resistant Pancreatic Cancer Cells Induced by MDR1 and MRP1 Overexpression in Vitro. Front Surg 2022; 9:890412. [PMID: 35656085 PMCID: PMC9152182 DOI: 10.3389/fsurg.2022.890412] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/27/2022] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Gemcitabine (GEM) is the first-line chemotherapeutic drug for pancreatic cancer treatment in clinical practice. However, many reasons can reduce the efficacy of GEM, among which the high expression of ATP-binding cassette (ABC) transporters is a significant factor. In this study, we aimed to investigate the antitumor effect of gemcitabine-loaded human serum albumin nanoparticle (GEM-HSA-NP) on GEM-resistant pancreatic cancer cells induced by the high expression of ABC transporters, namely multidrug resistance protein 1/P-gp/ABCB1 (MDR1) and multidrug resistance-associated protein 1/ ABCC1 (MRP1). METHODS MDR1 and MRP1 were stably overexpressed via lentiviral transduction in the pancreatic cancer cell lines BxPC3 and PANC1. Proliferation inhibition assays, cell cycle arrest and apoptosis analyses were conducted to examine the antitumor effect of GEM-HSA-NP. In addition, intracellular ATP levels were determined to explore the potential mechanisms implicated preliminarily. RESULTS When administered to GEM-resistant cancer cells, GEM-HSA-NP displayed its antitumor effect by promoting the inhibition of proliferation, cell cycle arrest, and apoptosis induction. Intracellular ATP depletion, caused by the albumin component of GEM-HSA-NP was proposed to be potentially involved in the modulation of ABC transporter activity. CONCLUSION GEM-HSA-NP can effectively overcome GEM-resistance induced by MDR1 and MRP1 overexpression, which highlights its potential value in a clinical setting.
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Affiliation(s)
| | | | | | | | | | | | | | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ji Li
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Xiang Y, Dai S, Li D, Zhu X, Su J, Chen B, Wu M. Brusatol inhibits the invasion and migration of pancreatic cancer cells by suppressing the NRF2/NF-κB/STAT3 signal cascade. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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18
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Sajjadur Rahman M, Kyeremateng J, Saha M, Asare S, Uddin N, Halim MA, Raynie DE. Evaluation of the experimental and computed properties of choline chloride-water formulated deep eutectic solvents. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2022.118520] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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19
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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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20
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Yehya AHS, Asif M, Abdul Majid AMS, Oon CE. Complementary effects of Orthosiphon stamineus standardized ethanolic extract and rosmarinic acid in combination with gemcitabine on pancreatic cancer. Biomed J 2021; 44:694-708. [PMID: 35166208 PMCID: PMC8847836 DOI: 10.1016/j.bj.2020.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.s) is used widely as a traditional medicine for the treatment of multiple ailments, including cancer in South East Asia. The present in vitro study was designed to investigate the complementary effects of an ethanolic extract of O.s (Et. O.s) or rosmarinic acid in combination with gemcitabine on Panc-1 pancreatic cancer cells. METHOD Cell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC50) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry. RESULTS Et. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain. CONCLUSION This study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.
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Affiliation(s)
- Ashwaq H S Yehya
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia.
| | - Muhammad Asif
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan.
| | - Amin M S Abdul Majid
- EMAN Testing and Research Laboratories, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Australia.
| | - Chern E Oon
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia.
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21
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Bartram T, Schütte P, Möricke A, Houlston RS, Ellinghaus E, Zimmermann M, Bergmann A, Löscher BS, Klein N, Hinze L, Junk SV, Forster M, Bartram CR, Köhler R, Franke A, Schrappe M, Kratz CP, Cario G, Stanulla M. Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia. J Clin Med 2021; 10:jcm10214815. [PMID: 34768335 PMCID: PMC8584334 DOI: 10.3390/jcm10214815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.
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Affiliation(s)
- Thies Bartram
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Peter Schütte
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Anja Möricke
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK;
| | - Eva Ellinghaus
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Martin Zimmermann
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Anke Bergmann
- Department of Human Genetics, Hannover Medical School, 30625 Hannover, Germany;
| | - Britt-Sabina Löscher
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Norman Klein
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Laura Hinze
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Stefanie V. Junk
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Michael Forster
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Claus R. Bartram
- Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (C.R.B.); (R.K.)
| | - Rolf Köhler
- Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (C.R.B.); (R.K.)
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, 24118 Kiel, Germany; (E.E.); (B.-S.L.); (M.F.); (A.F.)
| | - Martin Schrappe
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Christian P. Kratz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
| | - Gunnar Cario
- Department of Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; (T.B.); (A.M.); (M.S.); (G.C.)
| | - Martin Stanulla
- Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; (P.S.); (M.Z.); (N.K.); (L.H.); (S.V.J.); (C.P.K.)
- Correspondence: ; Tel.: +49-511-532-7978
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22
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Basu M, Philipp LM, Baines JF, Sebens S. The Microbiome Tumor Axis: How the Microbiome Could Contribute to Clonal Heterogeneity and Disease Outcome in Pancreatic Cancer. Front Oncol 2021; 11:740606. [PMID: 34631577 PMCID: PMC8495218 DOI: 10.3389/fonc.2021.740606] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by a poor prognosis with a 5-year survival rate of only around 10% and an ongoing increase in death rate. Due to the lack of early and specific symptoms, most patients are diagnosed at an advanced or even metastasized stage, essentially limiting curative treatment options. However, even curative resection of the primary tumor and adjuvant therapy often fails to provide a long-term survival benefit. One reason for this dismal situation can be seen in the evolution of therapy resistances. Furthermore, PDAC is characterized by high intratumor heterogeneity, pointing towards an abundance of cancer stem cells (CSCs), which are regarded as essential for tumor initiation and drug resistance. Additionally, it was shown that the gut microbiome is altered in PDAC patients, promotes Epithelial-Mesenchymal-Transition (EMT), determines responses towards chemotherapy, and affects survival in PDAC patients. Given the established links between CSCs and EMT as well as drug resistance, and the emerging role of the microbiome in PDAC, we postulate that the composition of the microbiome of PDAC patients is a critical determinant for the abundance and plasticity of CSC populations and thus tumor heterogeneity in PDAC. Unravelling this complex interplay might pave the way for novel treatment strategies.
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Affiliation(s)
- Meghna Basu
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute of Experimental Medicine, Kiel University, Kiel, Germany
| | - Lisa-Marie Philipp
- Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel University, Kiel, Germany
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute of Experimental Medicine, Kiel University, Kiel, Germany
| | - Susanne Sebens
- Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel University, Kiel, Germany
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23
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Fallah M, Davoodvandi A, Nikmanzar S, Aghili S, Mirazimi SMA, Aschner M, Rashidian A, Hamblin MR, Chamanara M, Naghsh N, Mirzaei H. Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer. Biomed Pharmacother 2021; 142:112024. [PMID: 34399200 PMCID: PMC8458260 DOI: 10.1016/j.biopha.2021.112024] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/01/2021] [Accepted: 08/07/2021] [Indexed: 02/07/2023] Open
Abstract
Silymarin contains a group of closely-related flavonolignan compounds including silibinin, and is extracted from Silybum marianum species, also called milk thistle. Silymarin has been shown to protect the liver in both experimental models and clinical studies. The chemopreventive activity of silymarin has shown some efficacy against cancer both in vitro and in vivo. Silymarin can modulate apoptosis in vitro and survival in vivo, by interfering with the expression of cell cycle regulators and apoptosis-associated proteins. In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity. The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in gastrointestinal cancers. This review examines the recent studies and summarizes the mechanistic pathways and down-stream targets of silymarin in the therapy of gastrointestinal cancer.
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Affiliation(s)
- Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shahin Nikmanzar
- Department of Neurosurgery, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sarehnaz Aghili
- Department of Gynecology and Obstetrics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Ali Mirazimi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10463, USA
| | - Amir Rashidian
- Department of Pharmacology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Mohsen Chamanara
- Department of Pharmacology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran; Toxicology Research Center, Aja University of Medical Sciences, Tehran, Iran.
| | - Navid Naghsh
- Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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24
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Teng X, Wang SY, Shi YQ, Fan XF, Liu S, Xing Y, Guo YY, Dong M. The role of emodin on cisplatin resistance reversal of lung adenocarcinoma A549/DDP cell. Anticancer Drugs 2021; 32:939-949. [PMID: 34001704 DOI: 10.1097/cad.0000000000001086] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Exploring drugs that reverse drug resistance and increase the sensitivity of chemotherapy drugs could significantly improve treatment effect of cancer. Our study explored the reversal effect and possible molecular mechanisms of emodin on cisplatin resistance in A549/DDP cells. The IC50 and resistance index of cells were determined by Cell Counting Kit-8 assay. The ability of cell proliferation was evaluated by wound healing assay. Transwell assay was used to detect cell invasion and migration. Apoptosis induction rate was determined by flow cytometry assay and 4',6- diamidino- 2-phenylindole staining. Intracellular concentration was determined by HPLC. Western blot analysis was applied to determine expressions of nuclear factor kappa beta (NF-κB) and its downstream proteins. In this study, we found that the growth inhibitory effect of cisplatin was significantly enhanced by emodin in A549/DDP cells. The combined use of emodin with DDP can effectively promote lung cancer cells apoptosis and inhibit cell migration and invasion. Further investigation indicated that reinforcement effect of emodin and DDP may be associated with inhibition of NF-κB pathway and drug efflux-related proteins such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and Glutathione S-transferase (GST). The key role of NF-κB was further confirmed by the application of NF-κB inhibitor Ammonium pyrrolidinedithiocarbamate. The intervention of both can significantly increase A549/DDP cell apoptosis and inhibit DDP-induced upregulation of P-gp, MRP and GST. Emodin reverses the cisplatin resistance of tumor cells by down-regulating expression of P-gp, MRP and GST, increasing the intracellular accumulation in A549/DDP cells, and the effect may be associated with the NF-κB pathways.
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Affiliation(s)
- Xue Teng
- Department of Pharmacy, Harbin Medical University Cancer Hospital
| | - Shu Ya Wang
- Department of Pharmacy, Harbin Medical University Cancer Hospital
| | - Yuan Qi Shi
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Xiao Fan Fan
- Department of Pharmacy, Harbin Medical University Cancer Hospital
| | - Shuang Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital
| | - Yue Xing
- Department of Pharmacy, Harbin Medical University Cancer Hospital
| | - Yuan Yuan Guo
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital
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25
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Xu H, Li Y, Paxton JW, Wu Z. Co-Delivery Using pH-Sensitive Liposomes to Pancreatic Cancer Cells: the Effects of Curcumin on Cellular Concentration and Pharmacokinetics of Gemcitabine. Pharm Res 2021; 38:1209-1219. [PMID: 34189639 DOI: 10.1007/s11095-021-03072-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE PEGylated pH-sensitive liposomes (PSL) dual-loaded with gemcitabine and curcumin were investigated for the potential application in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) treatment. Curcumin was employed as an inhibitor of the efflux transporter, multidrug resistance protein 5 (MRP5) in PDAC cells. METHODS Liposomes were prepared with gemcitabine in the core and curcumin in the bilayers. The effects of curcumin on pH-sensitivity and 'endosome escape' of PSL with different PEGylation were investigated using a calcein self-quench assay. The effects of curcumin on intracellular gemcitabine concentrations, and cytotoxicity to a MIA PaCa-2 PDAC cell line was evaluated. The pharmacokinetics were investigated in rats following intravenous injection. RESULTS The addition of curcumin to the PSL bilayers (0.2-1 mol%)slightly decreased the pH-sensitivity of PSL, but to a less extent than PEGylation (0-5 mol%). Co-treatment with curcumin increased gemcitabine cellular accumulation in a concentration-dependent manner, and resulted in synergistic cytotoxicity towards MIA PaCa-2cells.Both these effects were augmented by the use of PSL, particularly when the two drugs were co-loaded in PSL. In rats, the dual-drug loaded PSL produced significantly reduced (p < 0.05) plasma clearance (CL) and volume of distribution (Vd) for both drugs, alongside 3 to 4-fold increases in the area-under-the-concentration-time curves compared to the free drugs. Additionally, curcumin slightly increase the plasma concentrations of gemcitabine possibly also via the MRP5 inhibition effect. CONCLUSION Co-delivery of curcumin with gemcitabine using PSL not only increased the intracellular gemcitabine concentration thus cytotoxicity to MIA PaCa-2 cells but also significantly improved the pharmacokinetic profiles for both drugs. Graphical Abstract.
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Affiliation(s)
- Hongtao Xu
- School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Yan Li
- Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
- Auckland University of Technology, Auckland, New Zealand
| | - James W Paxton
- Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Zimei Wu
- School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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26
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Kasikci E, Aydemir E, Yogurtcu BM, Sahin F, Bayrak OF. Repurposing of Alexidine Dihydrochloride as an Apoptosis Initiator and Cell Cycle Inhibitor in Human Pancreatic Cancer. Anticancer Agents Med Chem 2021; 20:1956-1965. [PMID: 32384037 DOI: 10.2174/1871520620666200508085439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 12/30/2019] [Accepted: 01/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine Dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1. METHODS After the IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods, including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured, and changes in the cell cycle were analyzed. RESULTS AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit the cell cycle in pancreatic cancer cell lines. CONCLUSION In conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.
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Affiliation(s)
- Ezgi Kasikci
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey,Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Esra Aydemir
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Bekir M Yogurtcu
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Fikrettin Sahin
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Omer F Bayrak
- Department of Medical Genetics, Yeditepe University Medical School and Yeditepe University Hospital, Istanbul 34718, Turkey
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27
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Thakur A, Ung J, Tomaszewski EN, Schienschang A, LaBrie TM, Schalk DL, Lum LG. Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness. Oncoimmunology 2021; 10:1930883. [PMID: 34123574 PMCID: PMC8172155 DOI: 10.1080/2162402x.2021.1930883] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/21/2021] [Accepted: 05/13/2021] [Indexed: 01/08/2023] Open
Abstract
In this study, we investigated the ability of bispecific antibody armed activated T cells to target drug resistant pancreatic cancer cells and whether or not "priming" these resistant cancer cells with bispecific antibody armed activated T cells could enhance subsequent responsiveness to chemotherapeutic drugs. Chemotherapeutic responses for pancreatic cancer are either limited or the tumors develop resistance to chemotherapy regimens. The impetus for this study was the remarkable clinical response seen in our earlier phase I/II clinical trial: a pancreatic cancer patient with drug resistant tumors who showed progression of disease following three infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) was restarted on the initial low dose of 5-fluorouracil showed complete response, suggesting that BATs infusions may have sensitized patient's tumor for chemoresponsiveness. In the current study, we tested the hypothesis that BATs can sensitize tumors for chemoresponsiveness. Gemcitabine or cisplatin-resistant MiaPaCa-2 and L3.6 cell lines were effectively targeted by EGFR BATs. Priming of drug sensitive or resistant cells with EGFR BATs followed by retargeting with lower concentrations of 50% inhibitory concentration of gemcitabine or cisplatin showed enhanced cytotoxicity. Gemcitabine or cisplatin-resistant cell lines show an increased proportion of CD44+/CD24+/EpCAM+ cancer stem like cells as well as an increased number of ABC transporter ABCG2 positive cells compared to the parental cell lines. These data suggest that bispecific antibody armed activated T cells can target and kill chemo-resistant tumor cells and also markedly augment subsequent chemotherapeutic responsiveness, possibly by modulating the expression of ABC transporters.
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Affiliation(s)
- Archana Thakur
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Johnson Ung
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Elyse N. Tomaszewski
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, Michigan, USA
| | - Amy Schienschang
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Timothy M. LaBrie
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Dana L. Schalk
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Lawrence G. Lum
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA
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28
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Tang M, Lozano Hernandez L, Reginald-Opara JN, Svirskis D, Leung E, Wang H, Wu Z. Zebularine suppressed gemcitabine-induced senescence and improved the cellular and plasma pharmacokinetics of gemcitabine, augmented by liposomal co-delivery. Int J Pharm 2021; 602:120659. [PMID: 33933647 DOI: 10.1016/j.ijpharm.2021.120659] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/17/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023]
Abstract
Chemoresistance is a major factor driving cancer recurrence. This study investigated the potential of zebularine, a dual cytidine deaminase (CDA)/epigenetic inhibitor, to circumvent gemcitabine-resistance in pancreatic cancer using a nanomedicine co-delivery approach. The mRNA expression of key metabolic enzymes, including CDA for gemcitabine deactivation in a gemcitabine-resistant cell line Gr2000 and its parental MIA PaCa-2 was compared using quantitative reverse transcription polymerase chain reaction. A highly gemcitabine-resistant population (HRP) in Gr2000 were characterised for their growth pattern, β-galactosidase activity (a hallmark of senescence) and chemosensitivity to zebularine after isolation. The CDA inhibition effects of zebularine on the intracellular gemcitabine accumulation and pharmacokinetics in rats when co-delivered with pH-sensitive liposomes (pSL) were investigated. Gr2000 had a 3-time upregulated mRNA expression and enzyme activity for CDA. The HRP (28% of bulk Gr2000) were predominately senescent cells which re-proliferated following a growth arrest for a week. Zebularine suppressed the regrowth of senescent cells, meanwhile enhanced cellular gemcitabine concentration by 2-fold. When co-delivered with pSL, zebularine increased cellular gemcitabine concentration by 4-fold, and extended the half-life of gemcitabine in plasma by 22-fold in rats. In conclusion, multiple mechanisms including therapy-induced senescence were identified with gemcitabine-resistance. Co-delivery of zebularine using liposomes could provide multifaceted benefits in gemcitabine therapy for pancreatic cancer treatment.
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Affiliation(s)
- Mingtan Tang
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Lina Lozano Hernandez
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Joy N Reginald-Opara
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Darren Svirskis
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Euphemia Leung
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Hongbo Wang
- School of Pharmacy, Yantai University, Yantai 264005, PR China
| | - Zimei Wu
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand.
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29
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Guo H, Liu F, Yang S, Xue T. Emodin alleviates gemcitabine resistance in pancreatic cancer by inhibiting MDR1/P-glycoprotein and MRPs expression. Oncol Lett 2020; 20:167. [PMID: 32934734 PMCID: PMC7471752 DOI: 10.3892/ol.2020.12030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Gemcitabine is a gold standard chemotherapeutic agent for pancreatic cancer. However, gemcitabine has limited effectiveness due to the short-term development of chemoresistance. Emodin, a natural anthraquinone derivative isolated from the roots of rheumatic palm leaves prevents immunosuppression and exerts anticancer effects. The present study aimed to evaluate the effect of emodin on gemcitabine resistance. Gemcitabine-resistant PANC-1 pancreatic cancer cell xenografts were established in athymic mice, which were randomly assigned into four treatments groups as follows: Gemcitabine group, Emodin group, Gemcitabine+Emodin group and Negative control group. Body weight, tumor volume and tumor weight were measured over the course of treatment. The effect of each treatment on tumor tissue proliferation and apoptosis from nude mice was evaluated by using immunohistochemistry. The effect of each treatment on the proliferation of gemcitabine-resistant PANC-1 cells was also determined by using the Cell Counting Kit-8. Then, reverse transcription-quantitative (RT-q) PCR and western blotting were used to detect the mRNA and protein expression, respectively, of multidrug resistance gene 1 (MDR1) and the drug resistance-related proteins MRP1 and MRP5. The function and expression level of DR1 gene product, p-glycoprotein, was also analysed by flow cytometry and RT-qPCR, respectively. The results demonstrated that the combination of gemcitabine and emodin significantly reduced xenograft volume and reduced tumor growth in mice compared with treatment with gemcitabine or emodin only. In addition, emodin treatment reduced resistance to gemcitabine, which was characterized by the downregulation of P-glycoprotein, MRP1 and MRP5 expression in the group receiving combination treatment. The level of P-glycoprotein was also decreased in the group treated with gemcitabine+emodin compared with the single treatment groups. Taken together, these results demonstrated that emodin enhanced gemcitabine efficacy in tumor treatment and alleviated gemcitabine resistance in PANC-1 cell xenografts in mice via suppressing MDR1/P-glycoprotein and MRP expression.
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Affiliation(s)
- Hongchun Guo
- Department of General Surgery, Shanxian Central Hospital, Heze, Shandong 274300, P.R. China
| | - Feng Liu
- Department of General Surgery, Shanxian Central Hospital, Heze, Shandong 274300, P.R. China
| | - Shuguang Yang
- Department of Neurosurgery, Shanxian Central Hospital, Heze, Shandong 274300, P.R. China
| | - Tao Xue
- Department of Trauma Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Masetto F, Chegaev K, Gazzano E, Mullappilly N, Rolando B, Arpicco S, Fruttero R, Riganti C, Donadelli M. MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118824. [PMID: 32828758 DOI: 10.1016/j.bbamcr.2020.118824] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/28/2020] [Accepted: 08/10/2020] [Indexed: 12/01/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells. After its encapsulation in liposomes for drug delivery the intracellular NO level increases and nitration associated to activity inhibition of the multidrug resistance associated protein 5 (MRP5; ABCC5) occurs. This results in GEM intracellular accumulation and enhanced apoptotic cell death in GEM-resistant PDAC cells, which express MRP5 at higher levels than GEM-sensitive cells. Our results support the development of a new anti-tumoral strategy to efficiently affect GEM-resistant PDAC cells based on the usage of NO-GEM pro-drugs.
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Affiliation(s)
- Francesca Masetto
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
| | | | | | - Nidula Mullappilly
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
| | - Barbara Rolando
- Department of Drug Science and Technology, University of Turin, Italy
| | - Silvia Arpicco
- Department of Drug Science and Technology, University of Turin, Italy
| | - Roberta Fruttero
- Department of Drug Science and Technology, University of Turin, Italy
| | | | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
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31
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Tinoush B, Shirdel I, Wink M. Phytochemicals: Potential Lead Molecules for MDR Reversal. Front Pharmacol 2020; 11:832. [PMID: 32636741 PMCID: PMC7317022 DOI: 10.3389/fphar.2020.00832] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/20/2020] [Indexed: 12/14/2022] Open
Abstract
Multidrug resistance (MDR) is one of the main impediments in the treatment of cancers. MDR cancer cells are resistant to multiple anticancer drugs. One of the major mechanisms of MDR is the efflux of anticancer drugs by ABC transporters. Increased activity and overexpression of these transporters are important causes of drug efflux and, therefore, resistance to cancer chemotherapy. Overcoming MDR is a fundamental prerequisite for developing an efficient treatment of cancer. To date, various types of ABC transporter inhibitors have been employed but no effective anticancer drug is available at present, which can completely overcome MDR. Phytochemicals can reverse MDR in cancer cells via affecting the expression or activity of ABC transporters, and also through exerting synergistic interactions with anticancer drugs by addressing additional molecular targets. We have listed numerous phytochemicals which can affect the expression and activity of ABC transporters in MDR cancer cell lines. Phytochemicals in the groups of flavonoids, alkaloids, terpenes, carotenoids, stilbenoids, lignans, polyketides, and curcuminoids have been examined for MDR-reversing activity. The use of MDR-reversing phytochemicals with low toxicity to human in combination with effective anticancer agents may result in successful treatment of chemotherapy-resistant cancer. In this review, we summarize and discuss published evidence for natural products with MDR modulation abilities.
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Affiliation(s)
- Boshra Tinoush
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
| | - Iman Shirdel
- Marine Sciences Faculty, Tarbiat Modares University, Noor, Iran
| | - Michael Wink
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
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32
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Aier I, Semwal R, Raj U, Varadwaj PK. Comparative modeling and structure based drug repurposing of PAX2 transcription factor for targeting acquired chemoresistance in pancreatic ductal adenocarcinoma. J Biomol Struct Dyn 2020; 39:2071-2078. [PMID: 32174259 DOI: 10.1080/07391102.2020.1742793] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a pancreatic malignancy suffering from poor prognosis; the worst among all types of cancer. Chemotherapy, which is the standard regime for treatment in most cases, is often rendered useless as drug resistance quickly sets in after prolonged exposure to the drug. The implication of PAX2 transcription factor in regulating several ATP-binding cassette (ABC) transporter proteins that are responsible for the acquisition of drug resistance in PDAC makes it a potential target for treatment purposes. In this study, the 3D structure of PAX2 protein was modeled, and the response of key amino acids to perturbation was identified. Subsequently, kappadione, a vitamin K derivative, was found to bind efficiently to PAX2 with a binding energy of -9.819 kcal/mol. The efficacy of mechanism and mode of binding was studied by docking the protein with DNA in the presence and absence of the drug. The presence of kappadione disrupted DNA binding with key effector resides, preventing the DNA from coming into contact with the binding region essential for protein translation. By occupying the DNA binding region and replacing it with a ligand, the mechanism by which DNA interacts with PAX2 could be manipulated. Inhibition of PAX2-DNA binding using kappadione and other small molecules can prove to be beneficial for combating chemoresistance in PDAC, as proposed through in silico approaches.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Imlimaong Aier
- Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India
| | - Rahul Semwal
- Department of Information Technology, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India
| | - Utkarsh Raj
- Department of Biotechnology and Bioinformatics, NIIT University, Rajasthan, India
| | - Pritish Kumar Varadwaj
- Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India
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33
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Ravindranathan P, Pasham D, Goel A. Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells. Carcinogenesis 2020; 40:412-421. [PMID: 30596962 DOI: 10.1093/carcin/bgy184] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 12/07/2018] [Accepted: 12/27/2018] [Indexed: 12/17/2022] Open
Abstract
Multidrug resistance is a major hindrance in managing cancer. By performing a series of experiments in chemoresistant colorectal cancer cell lines, we demonstrate that oligomeric proanthocyanidins (OPCs) from grape seed extracts can sensitize both acquired (HCT116-FOr cells) and innately chemoresistant (H716 cells) cancer cells to chemotherapeutic drugs, 5-fluorouracil (5FU) and oxaliplatin, by inhibiting adenosine triphosphate-binding cassette (ABC) transporter proteins. When combined with chemotherapeutic drugs, OPCs significantly inhibited growth of the chemoresistant cells (P < 0.05 to < 0.001) and decreased the expression of several key ABC transporters. Moreover, the activity of the ABC transporters was also significantly decreased by OPCs in the cell lines (P < 0.05). We further confirmed that co-treatment with OPCs sensitized the chemoresistant cells to 5FU and oxaliplatin, as observed by improvement in cell cycle arrest, double-strand breaks and p53 accumulation in these cells. In addition, we confirmed that co-administration of OPCs with chemotherapeutic drugs significantly decreased chemoresistant xenograft tumor growth in mice (P < 0.05). Together, our study illuminates the downregulation of multiple ABC transporters as a mechanism by which OPCs overcome chemoresistance in cancer cells and may serve as adjunctive treatments in patients with refractory colorectal cancer.
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Affiliation(s)
- Preethi Ravindranathan
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute, and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Divya Pasham
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute, and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
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Nobili S, Lapucci A, Landini I, Coronnello M, Roviello G, Mini E. Role of ATP-binding cassette transporters in cancer initiation and progression. Semin Cancer Biol 2020; 60:72-95. [PMID: 31412294 DOI: 10.1016/j.semcancer.2019.08.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 12/18/2022]
Abstract
ATP Binding Cassette (ABC) transporters, widely studied in cancer for their role in drug resistance, have been more recently also considered for their contribution to cancer cell biology. To date, many data provide evidences for their potential role in all the phases of cancer development from cancer susceptibility, tumor initiation, tumor progression and metastasis. Although many evidences are based on correlative analyses, data describing a direct or indirect role of ABC transporters in cancer biology are increasing. Overall, current available information suggests a relevant molecular effector role of some ABC transporters in cancer invasion and metastasis as reported in experimental tumor models. From a therapeutic point of view, due to the physiological relevant roles that ABC transporters play in the organism, the capability to selectively inhibit the function or the expression of ABC transporters in cancer stem cells or other tumor cells, represents the main challenge for researcher scientists. A detailed and updated description of the current knowledge on the role of ABC transporters in cancer biology is provided.
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Affiliation(s)
- Stefania Nobili
- Department of Health Sciences, University of Florence, Florence, Italy.
| | - Andrea Lapucci
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, Florence, Italy
| | | | | | - Enrico Mini
- Department of Health Sciences, University of Florence, Florence, Italy
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35
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Mao X, He Z, Zhou F, Huang Y, Zhu G. Prognostic significance and molecular mechanisms of adenosine triphosphate-binding cassette subfamily C members in gastric cancer. Medicine (Baltimore) 2019; 98:e18347. [PMID: 31852133 PMCID: PMC6922578 DOI: 10.1097/md.0000000000018347] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the major leading causes of tumor-related deaths worldwide. Adenosine triphosphate-binding cassette subfamily C (ABCC) consists of 13 members, ABCC1 to 13, which were examined for their associations with GC.The online Kaplan-Meier Plotter database was used to determine the prognostic significance of ABCC subfamily members in GC. Stratified analyses were performed using gender, disease stage, degree of tumor differentiation, expression of human epidermal growth factor receptor 2 (HER2), and Lauren classification. Molecular mechanisms were examined using the database for annotation, visualization, and integrated discovery database.ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 expression showed prognostic significance in the whole population and in male and female subpopulations (all P ≤ .05). Furthermore, high expression of most ABCC family members always suggested a poor prognosis, except for ABCC7 (P > .05). Stratified analyses revealed that ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 expression showed prognostic significance for the whole population, as well as male and female populations. ABCC2 and ABCC9 were significantly correlated with all disease stages, while ABCC2 and ABCC6 were significantly correlated with all Lauren classifications. Expression of ABCC1, ABCC3, ABCC5, ABCC7, ABCC8, ABCC9, and ABCC10 was significantly correlated with either negative or positive of HER2 status (all P ≤ .05). Enrichment analysis indicated that these genes were involved in ATPase activity, transmembrane transport, or were ABC transporters (all P ≤ .05).ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 may be potential prognosis biomarkers for GC, acting as ABC transporters and via ATPase activity.
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Affiliation(s)
- Xianshuang Mao
- Department of Hepatobiliary Gastrointestinal Surgery, The People's Hospital of Hezhou City, Hezhou
| | - Zhenhua He
- Department of Hepatobiliary Gastrointestinal Surgery, The People's Hospital of Hezhou City, Hezhou
| | - Fengsheng Zhou
- Department of Hepatobiliary Gastrointestinal Surgery, The People's Hospital of Hezhou City, Hezhou
| | - Yongchu Huang
- Department of Hepatobiliary Gastrointestinal Surgery, The People's Hospital of Hezhou City, Hezhou
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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36
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Aier I, Semwal R, Dhara A, Sen N, Varadwaj PK. An integrated epigenome and transcriptome analysis identifies PAX2 as a master regulator of drug resistance in high grade pancreatic ductal adenocarcinoma. PLoS One 2019; 14:e0223554. [PMID: 31622355 PMCID: PMC6797122 DOI: 10.1371/journal.pone.0223554] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.
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Affiliation(s)
- Imlimaong Aier
- Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India
| | - Rahul Semwal
- Department of Information Technology, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India
| | - Aiindrila Dhara
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
| | - Nirmalya Sen
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
- S.N.Bose Innovation Centre, University Of Kalyani, Nadia, West Bengal, India
| | - Pritish Kumar Varadwaj
- Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India
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37
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Adamska A, Domenichini A, Capone E, Damiani V, Akkaya BG, Linton KJ, Di Sebastiano P, Chen X, Keeton AB, Ramirez-Alcantara V, Maxuitenko Y, Piazza GA, De Laurenzi V, Sala G, Falasca M. Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:312. [PMID: 31378204 PMCID: PMC6681491 DOI: 10.1186/s13046-019-1308-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 07/02/2019] [Indexed: 12/20/2022]
Abstract
Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis. Methods To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC. Results Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. Conclusions Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1308-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia
| | - Alice Domenichini
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia
| | - Emily Capone
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Verena Damiani
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Begum Gokcen Akkaya
- Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK
| | - Kenneth J Linton
- Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK
| | - Pierluigi Di Sebastiano
- Department of Surgery, Unit of Surgical Oncology, SS. Annunziata Hospital, G. D'Annunzio University, I-66100, Chieti, Italy
| | - Xi Chen
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Adam B Keeton
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | | | - Yulia Maxuitenko
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Gary A Piazza
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Vincenzo De Laurenzi
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.,Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Gianluca Sala
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia. .,Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK.
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Lowrence RC, Subramaniapillai SG, Ulaganathan V, Nagarajan S. Tackling drug resistance with efflux pump inhibitors: from bacteria to cancerous cells. Crit Rev Microbiol 2019; 45:334-353. [PMID: 31248314 DOI: 10.1080/1040841x.2019.1607248] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug resistance is a serious concern in a clinical setting jeopardizing treatment for both infectious agents and cancers alike. The wide-spread emergence of multi-drug resistant (MDR) phenotypes from bacteria to cancerous cells necessitates the need to target resistance mechanisms and prevent the emergence of resistant mutants. Drug efflux seems to be one of the preferred approaches embraced by both microbial and mammalian cells alike, to thwart the action of chemotherapeutic agents thereby leading to a drug resistant phenotype. Relative to microbes, which predominantly employs proton motive force (PMF) powered, Major Facilitator Superfamily (MFS)/Resistance Nodulation and Division (RND) classes of efflux pumps to efflux drugs, cancerous cells preferentially use ATP fuelled ATP binding cassette (ABC) transporters to extrude chemotherapeutic agents. The prevalence, evolutionary characteristics and overlapping functions of ABC transporters have been highlighted in this review. Additionally, we outline the role of ABC pumps in conferring MDR phenotype to both bacteria and cancerous cells and underscore the importance of efflux pump inhibitors (EPI) to mitigate drug resistance. Based on the literature reports and analysis, we reason out feasibility of employing bacteria as a tool to screen for EPI's targeting ABC pumps of cancerous cells.
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Affiliation(s)
- Rene Christena Lowrence
- a Department of Molecular Biology and Biotechnology, University of Sheffield , Sheffield , UK
| | | | | | - Saisubramanian Nagarajan
- c Department of Biotechnology, School of Chemical and Biotechnology, SASTRA Deemed to be University , Thanjavur , India
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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40
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Gentiluomo M, Puchalt García P, Galeotti AA, Talar-Wojnarowska R, Tjaden C, Tavano F, Strobel O, Kupcinskas J, Neoptolemos J, Hegyi P, Costello E, Pezzilli R, Sperti C, Lawlor RT, Capurso G, Szentesi A, Soucek P, Vodicka P, Lovecek M, Hackert T, Cavestro GM, Milanetto AC, Canzian F, Campa D. Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients. Carcinogenesis 2019; 40:544-550. [PMID: 30629142 DOI: 10.1093/carcin/bgz006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/11/2018] [Accepted: 01/08/2019] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.
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Affiliation(s)
- Manuel Gentiluomo
- Department of Biology, University of Pisa, Pisa, Italy
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Paula Puchalt García
- Department of Biology, University of Pisa, Pisa, Italy
- Universitat Politècnica de Valéncia, Valencia, Spain
| | - Alice Alessandra Galeotti
- Department of Biology, University of Pisa, Pisa, Italy
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Christine Tjaden
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Juozas Kupcinskas
- Department of Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - John Neoptolemos
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Péter Hegyi
- Translational Gastroenterology Research Group, Hungarian Academy of Sciences and University of Szeged (MTA-SZTE), Szeged, Hungary
- Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- Department of Translational Medicine, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Eithne Costello
- National Institute for Health Research Liverpool, Pancreas Biomedical Research Unit, University of Liverpool, United Kingdom
| | - Raffaele Pezzilli
- Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital Bologna, Italy
| | - Cosimo Sperti
- Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy
| | - Rita T Lawlor
- ARC-Net Research Centre, University Hospital G.B. Rossi, University of Verona, Verona, Italy
| | - Gabriele Capurso
- Pancreatico/Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
- Digestive and Liver Disease Unit, S. Andrea Hospital, Rome, Italy
| | - Andrea Szentesi
- Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
- János Szentágothai Research Centre and Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Pavel Soucek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Vodicka
- Institute of Experimental Medicine, Czech Academy of Sciences and Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
| | - Martin Lovecek
- Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Czech Republic
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University San Raffaele Scientific Institute, Milan, Italy
| | - Anna Caterina Milanetto
- Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
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41
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ABCC3 is a novel target for the treatment of pancreatic cancer. Adv Biol Regul 2019; 73:100634. [PMID: 31053501 DOI: 10.1016/j.jbior.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 04/23/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease, lacking effective therapeutic approaches and leaving PDAC patients with a poor prognosis. The life expectancy of PDAC patients has not experienced a significant change in the last few decades with a five-year survival rate of only 8%. To address this unmet need, novel pharmacological targets must be identified for clinical intervention. ATP Binding Cassette (ABC) transporters are frequently overexpressed in different cancer types and represent one of the major mechanisms responsible for chemoresistance. However, a more direct role for ABC transporters in tumorigenesis has not been widely investigated. Here, we show that ABCC3 (ABC Subfamily C Member 3; previously known as MRP3) is overexpressed in PDAC cell lines and also in clinical samples. We demonstrate that ABCC3 expression is regulated by mutant p53 via miR-34 and that the transporter drives PDAC progression via transport of the bioactive lipid lysophosphatidylinositol (LPI). Disruption of ABCC3 function either by genetic knockdown reduces pancreatic cancer cell growth in vitro and in vivo. Mechanistically, we demonstrate that knockdown of ABCC3 reduce cell proliferation by inhibition of STAT3 and HIF1α signalling pathways, previously been shown to be key regulators of PDAC progression. Collectively, our results identify ABCC3 as a novel and promising target in PDAC therapy.
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Li D, Qian X, Xu P, Wang X, Li Z, Qian J, Yao J. Identification of lncRNAs and Their Functional Network Associated with Chemoresistance in SW1990/GZ Pancreatic Cancer Cells by RNA Sequencing. DNA Cell Biol 2018; 37:839-849. [PMID: 30113217 DOI: 10.1089/dna.2018.4312] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Duguang Li
- The Second Clinical College of Dalian Medical University, Dalian, China
| | - Xiaowei Qian
- Yangzhou University Medical College, Yangzhou, China
| | - Peng Xu
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou, China
| | - Xiaodong Wang
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou, China
| | - Zhennan Li
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou, China
| | - Jianjun Qian
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou, China
| | - Jie Yao
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou, China
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43
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Dauer P, Sharma NS, Gupta VK, Nomura A, Dudeja V, Saluja A, Banerjee S. GRP78-mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells. Mol Oncol 2018; 12:1498-1512. [PMID: 29738634 PMCID: PMC6120253 DOI: 10.1002/1878-0261.12322] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/10/2018] [Accepted: 04/16/2018] [Indexed: 01/21/2023] Open
Abstract
Chemoresistance is a major therapeutic challenge that plays a role in the poor statistical outcomes in pancreatic cancer. Unfolded protein response (UPR) is one of the homeostasis mechanisms in cancer cells that have been correlated with chemoresistance in a number of cancers including pancreatic cancer. In this study, we show that modulating glucose regulatory protein 78 (GRP78), the master regulator of the UPR, can have a profound effect on multiple pathways that mediate chemoresistance. Our study showed for the first time that silencing GRP78 can diminish efflux activity of ATP-binding cassette (ABC) transporters, and it can decrease the antioxidant response resulting in an accumulation of reactive oxygen species (ROS). We also show that these effects can be mediated by the activity of specificity protein 1 (SP1), a transcription factor overexpressed in pancreatic cancer. Thus, inhibition of SP1 negatively affects the UPR, deregulates the antioxidant response of NRF2, as well as ABC transporter activity by inhibiting GRP78-mediated ER homeostasis. Sp1 and NRF2 have been classified as nononcogene addiction genes and thus are imperative to understanding the molecular mechanism of resistance. These finding have huge clinical relevance as both Sp1 and GRP78 are overexpressed in pancreatic cancer patients and increased expression of these proteins is indicative of poor prognosis. Understanding how these proteins may regulate chemoresistance phenotype of this aggressive cancer may pave the way for development of efficacious therapy for this devastating disease.
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Affiliation(s)
- Patricia Dauer
- Department of PharmacologyUniversity of MinnesotaMinneapolisMNUSA
| | - Nikita S. Sharma
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
| | - Vineet K. Gupta
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
| | - Alice Nomura
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
| | - Vikas Dudeja
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
| | - Ashok Saluja
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
| | - Sulagna Banerjee
- Department of SurgeryUniversity of MiamiFLUSA
- Sylvester Comprehensive Cancer CenterMiamiFLUSA
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Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
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45
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Yao L, Gu J, Mao Y, Zhang X, Wang X, Jin C, Fu D, Li J. Dynamic quantitative detection of ABC transporter family promoter methylation by MS-HRM for predicting MDR in pancreatic cancer. Oncol Lett 2018; 15:5602-5610. [PMID: 29552197 PMCID: PMC5840752 DOI: 10.3892/ol.2018.8041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 09/01/2017] [Indexed: 12/11/2022] Open
Abstract
The main focus of the present study was to evaluate whether ABC transporter family promoter methylation predicted multidrug resistance in gemcitabine-resistant cancer cell lines (BxPC-3/Gem and PANC-1/Gem). Using low concentrations of gemcitabine, the cell lines acquired drug resistance with different initial gemcitabine concentrations. A novel technology, methylation-sensitive high-resolution melting, was used to monitor the dynamic changes of ABC transporter family promoter methylation, including ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C (ABCC) and ATP binding cassette subfamily G member 2 (ABCG2) mRNA expression. It was revealed that, with elevation of initial gemcitabine concentration, expression of ABCB1, ABCC and ABCG2 mRNA and corresponding downstream proteins was increased while promoter methylation was decreased. These discoveries indicate that promoter methylation of ABCB1, ABCC and ABCG2 may be a valuable indicator of drug-resistance characteristics in BxPC-3/Gem and PANC-1/Gem cells via quantitative and simultaneous detection. These results also implied that MDR in pancreatic cancer not only arises from gene mutation, but also originates from promoter methylation.
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Affiliation(s)
- Lie Yao
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jichun Gu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Yishen Mao
- Department of Clinical Medicine, Fudan University, Shanghai 200082, P.R. China
| | - Xinju Zhang
- Central Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xiaoyi Wang
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Chen Jin
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Ji Li
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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46
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Natural Products for the Management and Prevention of Breast Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:8324696. [PMID: 29681985 PMCID: PMC5846366 DOI: 10.1155/2018/8324696] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/18/2017] [Accepted: 01/16/2018] [Indexed: 12/21/2022]
Abstract
Among all types of cancer, breast cancer is one of the most challenging diseases, which is responsible for a large number of cancer related deaths. Hormonal therapy, surgery, chemotherapy, and radiotherapy have been used as treatment of breast cancer, for a very long time. Due to severe side effects and multidrug resistance, these treatment approaches become increasingly ineffective. However, adoption of complementary treatment approach can be a big solution for this situation, as it is evident that compounds derived from natural source have a great deal of anticancer activity. Natural compounds can fight against aggressiveness of breast cancer, inhibit cancerous cell proliferation, and modulate cancer related pathways. A large number of research works are now focusing on the natural and dietary compounds and trying to find out new and more effective treatment strategies for the breast cancer patients. In this review, we discussed some significant natural chemical compounds with their mechanisms of actions, which can be very effective against the breast cancer and can be more potent by their proper modifications and further clinical research. Future research focusing on the natural anti-breast-cancer agents can open a new horizon in breast cancer treatment, which will play a great role in enhancing the survival rate of breast cancer patients.
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Mazza T, Copetti M, Capocefalo D, Fusilli C, Biagini T, Carella M, De Bonis A, Mastrodonato N, Piepoli A, Pazienza V, Maiello E, di Mola FF, di Sebastiano P, Andriulli A, Tavano F. MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater's papilla adenocarcinoma. Oncotarget 2017; 8:105320-105339. [PMID: 29285254 PMCID: PMC5739641 DOI: 10.18632/oncotarget.22184] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 07/11/2017] [Indexed: 01/06/2023] Open
Abstract
MiRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater's papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC.
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Affiliation(s)
- Tommaso Mazza
- Unit of Bioinformatics, Research Hospital, San Giovanni Rotondo 71013, Italy
| | | | - Daniele Capocefalo
- Unit of Bioinformatics, Research Hospital, San Giovanni Rotondo 71013, Italy
- Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome 00161, Italy
| | - Caterina Fusilli
- Unit of Bioinformatics, Research Hospital, San Giovanni Rotondo 71013, Italy
| | - Tommaso Biagini
- Unit of Bioinformatics, Research Hospital, San Giovanni Rotondo 71013, Italy
| | - Massimo Carella
- Medical Genetics Unit, Research Hospital, San Giovanni Rotondo 71013, Italy
| | - Antonio De Bonis
- Department of Surgery, Research Hospital, San Giovanni Rotondo 71013, Italy
| | | | - Ada Piepoli
- Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo 71013, Italy
| | - Valerio Pazienza
- Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo 71013, Italy
| | - Evaristo Maiello
- Department of Oncology IRCCS “Casa Sollievo della Sofferenza”, Research Hospital, San Giovanni Rotondo 71013, Italy
| | | | | | - Angelo Andriulli
- Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo 71013, Italy
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo 71013, Italy
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48
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Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis 2017; 38:1036-1046. [PMID: 29048549 DOI: 10.1093/carcin/bgx065] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/19/2017] [Indexed: 01/01/2023] Open
Abstract
Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed 'cancer stem cells' (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. However, the underlying mechanisms for curcumin-mediated chemosensitization remain unclear. The Enhancer of Zeste Homolog-2 (EZH2) subunit of Polycomb Repressive Complex 2 (PRC2) was recently identified as a key player regulating drug resistance. EZH2 mediates interaction with several long non-coding RNAs (lncRNAs) to modulate epithelial-mesenchymal transition and cancer stemness, phenomena commonly associated with drug resistance. Here, we report the re-sensitization of chemoresistant PDAC cells by curcumin through the inhibition of the PRC2-PVT1-c-Myc axis. Using gemcitabine-resistant PDAC cell lines, we found that curcumin sensitized chemoresistant cancer cells by inhibiting the expression of the PRC2 subunit EZH2 and its related lncRNA PVT1. Curcumin was also found to prevent the formation of spheroids, a hallmark of CSCs, and to down-regulate several self-renewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC.
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Affiliation(s)
- Kazuhiro Yoshida
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Shusuke Toden
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Preethi Ravindranathan
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Haiyong Han
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
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49
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Hesler RA, Huang JJ, Starr MD, Treboschi VM, Bernanke AG, Nixon AB, McCall SJ, White RR, Blobe GC. TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. Carcinogenesis 2017; 37:1041-1051. [PMID: 27604902 DOI: 10.1093/carcin/bgw093] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 08/16/2016] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.
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Affiliation(s)
| | | | - Mark D Starr
- Division of Medical Oncology, Department of Medicine
| | | | | | | | | | - Rebekah R White
- Department of Surgery, Duke University, B354 LSRC Research Drive , Box 91004, Durham, NC 27708 , USA
| | - Gerard C Blobe
- Department of Pharmacology and Cancer Biology.,Division of Medical Oncology, Department of Medicine
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50
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Rady M, Mostageer M, Rohde J, Zaghloul A, Knüchel-Clarke R, Saad S, Attia D, Mahran L, Spahn-Langguth H. Therapy-relevant aberrant expression of MRP3 and BCRP mRNA in TCC-/SCC-bladder cancer tissue of untreated patients. Oncol Rep 2017; 38:551-560. [DOI: 10.3892/or.2017.5695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 04/03/2017] [Indexed: 11/06/2022] Open
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