title: Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase.
abstract: New agent development, mechanistic understanding, and combinatorial partnerships with known and novel modalities continue to be important in the study of pancreatic cancer and its improved treatment. In this study, known antimetabolite drugs such as gemcitabine (ribonucleotide reductase inhibitor) and 5-fluorouracil (thymidylate synthase inhibitor) were compared with novel members of these two drug families in the treatment of a chemoresistant pancreatic cancer cell line PANC-1. Cellular survival data, along with protein and messenger ribonucleic acid expression for survivin, XIAP, cIAP1, and cIAP2, were compared from both the cell cytoplasm and from exosomes after single modality treatment. While all antimetabolite drugs killed PANC-1 cells in a time- and dose-dependent manner, neither family significantly altered the cytosolic protein level of the four inhibitors of apoptosis (IAPs) investigated. Survivin, XIAP, cIAP1, and cIAP2 were found localized to exosomes where no significant difference in expression was recorded. This inability for significant and long-lasting expression may be a reason why pancreatic cancer lacks responsiveness to these and other cancer-killing agents. Continued investigation is required to determine the responsibilities of these IAPs in their role in chemoresistance in pancreatic adenocarcinoma.
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Malyn M
authors.initials: MM
authors.lastname: Asuncion Valenzuela
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Imilce
authors.initials: I
authors.lastname: Castro
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Gonda
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Diaz Osterman
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Jutzy
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Aspe
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Salma
authors.initials: S
authors.lastname: Khan
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Neidigh
authors.affiliation: Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wall
keywords: 5-fluorodeoxyuridine; 5-fluorouracil; IAPs; antimetabolites; cladribine; exosomes; gemcitabine; hydroxyurea; pancreatic cancer