Collateral sensitivity as a strategy against cancer multidrug resistance

Drug Resist Updat. Feb-Apr 2012;15(1-2):98-105. doi: 10.1016/j.drup.2012.03.002. Epub 2012 Apr 6.

Abstract

While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Biological Transport / drug effects
  • Calcium Channel Blockers / therapeutic use
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Energy Metabolism / drug effects
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Prognosis
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Reactive Oxygen Species / metabolism
  • Verapamil / therapeutic use

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Calcium Channel Blockers
  • Protein Isoforms
  • Reactive Oxygen Species
  • Verapamil