Natural compound Oblongifolin C confers gemcitabine resistance in pancreatic cancer by downregulating Src/MAPK/ERK pathways

Cell Death Dis. 2018 May 1;9(5):538. doi: 10.1038/s41419-018-0574-1.

Abstract

Gemcitabine (GEM)-induced drug resistance is the major reason for the failure of chemotherapy in pancreatic cancer (PC). In this study, we found that Oblongifolin C (OC) efficiently inhibited PC cell proliferation by inducing G0/G1 arrest and apoptosis. Also, our mechanism study demonstrated that OC re-sensitized the GEM-resistant PC cells through the ubiquitin-proteasome-dependent degradation of Src, and then downregulating the MAPK pathway. Knockdown of Src plus OC resulted in a greater inhibitory effect in GEM-resistant PC cells. In contrast, Src overexpression reversed OC-mediated chemosensitization, thereby implicating Src in the action of OC. Moreover, our in vivo study showed that OC suppressed the tumor growth via the downregulation of Src, and enhanced the chemosensitivity of GEM-resistant PC to GEM. Overall, our results have revealed that OC is applicable as a promising agent for overcoming GEM-resistant PC, especially with aberrant Src expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Down-Regulation / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Terpenes / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Terpenes
  • oblongifolin C
  • Deoxycytidine
  • Gemcitabine