Cyclooxygenase-2: potential role in regulation of drug efflux and multidrug resistance phenotype

Curr Pharm Des. 2004;10(6):647-57. doi: 10.2174/1381612043453117.

Abstract

Multidrug resistance (MDR) of cancer cells to cytostatic agents is the major obstacle for the succesfull chemotherapy. One of the causes of the development of cellular resistance to a wide variety of drugs is the elevated expression of membrane transporter proteins such as members of ATP binding cassette (ABC) protein superfamily. Expression of the ABC transporter MDR1, also termed P-glycoprotein (P-gp), seems to correlate with drug resistance of tumors to chemotherapy. Cyclooxygenase-2, an inducible isoform of enzyme, responsible for generation of prostaglandins from arachidonic acid, is constitutively expressed in a number of cancer cells. Anti-cancer potency of cyclooxygenase inhibitors is established, but the mechanism of Cox-2-dependent potentiation of tumor growth is a subject of intense discussion. Here we focus on the discussion of potential link between Cox-2 expression and development of multidrug resistance phenotype. Our observation, that enforced expression of Cox-2 causes enhancement in MDR1 expression and functional activity suggests the existence of causal link between Cox-2 activity and MDR1 expression. The use of Cox-2 inhibitors to decrease function of MDR1 may enhance accumulation of chemotherapy agents and decrease resistance of tumors to chemotherapeutic drugs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / therapeutic use
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phenotype
  • Prostaglandin-Endoperoxide Synthases / metabolism*

Substances

  • ATP-Binding Cassette Transporters
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases