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Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase

Malyn M Asuncion Valenzuela1, Imilce Castro1, Amber Gonda1

  • 1Center for Health Disparities and Molecular Medicine, Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.

Oncotargets and Therapy
|March 14, 2015
PubMed

Insights

Novel antimetabolite drugs show potential against chemoresistant pancreatic cancer. However, key apoptosis inhibitors (IAPs) were not significantly altered, suggesting a mechanism for treatment resistance in pancreatic adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pancreatic cancer treatment is challenging due to chemoresistance.
  • Antimetabolite drugs are a cornerstone of chemotherapy.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To compare novel antimetabolite drugs with gemcitabine and 5-fluorouracil against chemoresistant pancreatic cancer cells (PANC-1).
  • To investigate the expression and localization of apoptosis inhibitors (IAPs) following antimetabolite treatment.

Main Methods:

  • Treatment of PANC-1 cells with various antimetabolite drugs.
  • Assessment of cellular survival via dose- and time-dependent assays.
  • Analysis of protein and mRNA expression of survivin, XIAP, cIAP1, and cIAP2 in cytosolic and exosomal fractions.

Main Results:

  • All tested antimetabolite drugs demonstrated time- and dose-dependent cytotoxicity against PANC-1 cells.
  • No significant alteration in cytosolic levels of survivin, XIAP, cIAP1, and cIAP2 was observed.
  • These IAPs were detected in exosomes, with no significant change in their expression levels.

Conclusions:

  • The lack of significant changes in IAP expression may contribute to pancreatic cancer's resistance to antimetabolite therapies.
  • Exosomal localization of IAPs warrants further investigation into their role in chemoresistance.
  • Further research is needed to elucidate the function of IAPs in pancreatic adenocarcinoma chemoresistance.
Keywords:
5-fluorodeoxyuridine5-fluorouracilIAPsantimetabolitescladribineexosomesgemcitabinehydroxyureapancreatic cancer

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