Cannabinoid receptor agonist as an alternative drug in 5-fluorouracil-resistant gastric cancer cells

Anticancer Res. 2013 Jun;33(6):2541-7.

Abstract

Fluorouracil is the main chemotherapeutic drug used for gastrointestinal cancers, which suffers the important problem of treatment resistance. There is little information whether cannabinoid agonists can be used as an alternative drug for fluorouracil-resistant gastric cancer cells. In this study, we investigated the effects of a cannabinoid agonist, WIN-55,212-2, on 5-fluorouracil (5-FU)-resistant human gastric cancer cells, to examine whether the cannabinoid agonist may be an alternative therapy. Survival of the 5-FU-resistant gastric cancer cell line, SNU-620-5FU/1000, was not significantly reduced even by a high dose of 5-FU treatment. However, WIN-55,212-2 inhibited the proliferation of SNU-620-5FU/1000 and enhanced their apoptosis, as indicated by an increase of apoptotic cell proportion, activated caspase-3 and Poly (ADP-ribose) polymerase cleavage. Furthermore, WIN-55,212-2 reduced phospho-extracellular-signal-regulated kinases (ERK) 1/2, phospho-Akt (protein kinase B), B-cell lymphoma-2 (BCL2) and BCL2-associated X (BAX) protein expression in 5-FU-resistant gastric cancer cells. These results indicate that a cannabinoid agonist may, indeed, be an alternative chemotherapeutic agent for 5-FU-resistant gastric cancer.

Keywords: Gastric cancer; apoptosis; cannabinoids; drug resistance; fluorouracil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzoxazines / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorouracil / pharmacology
  • Humans
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Cannabinoid / metabolism*
  • Stomach Neoplasms / drug therapy*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Morpholines
  • Naphthalenes
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cannabinoid
  • bcl-2-Associated X Protein
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 3
  • Fluorouracil