title: Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of malignancies, in large measure, due to the propensity of PDAC cells to acquire resistance to chemotherapeutic agents. A better understanding of the molecular basis of acquired resistance is a major focus of contemporary PDAC research. We report here the results of a study to independently develop cisplatin resistance in two distinct parental PDAC cell lines, AsPC1 and BxPC3, and to subsequently examine the molecular mechanisms associated with the acquired resistance. Cisplatin resistance in both resistant cell lines was found to be multifactorial and to be associated with mechanisms related to drug transport, drug inactivation, DNA damage response, DNA repair and the modulation of apoptosis. Our results demonstrate that the two resistant cell lines employed alternative molecular strategies in acquiring resistance dictated, in part, by pre-existing molecular differences between the parental cell lines. Collectively, our findings indicate that strategies to inhibit or reverse acquired resistance of PDAC cells to cisplatin, and perhaps other chemotherapeutic agents, may not be generalized but will require individual molecular profiling and analysis to be effective.
authors.affiliation: Integrated Cancer Research Center, School of Biological Sciences, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mezencev
authors.affiliation: Integrated Cancer Research Center, School of Biological Sciences, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Matyunina
authors.affiliation: Integrated Cancer Research Center, School of Biological Sciences, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: G T
authors.initials: GT
authors.lastname: Wagner
authors.affiliation: Integrated Cancer Research Center, School of Biological Sciences, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: McDonald
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin