Relevance of multidrug resistance in the age of targeted therapy

D. Türk, G. Szakács

Research output: Contribution to journalReview article

52 Citations (Scopus)

Abstract

Targeted drugs inhibit specific pathways that contribute to the malignant phenotype of cancer cells. The initial success of molecularly targeted therapies raised hope that newly developed agents would evade the general mechanisms of resistance that have reduced the efficacy of traditional anticancer drugs. In recent years, ATP-binding cassette (ABC) transporters related to multidrug resistance (MDR), such as P-glycoprotein (P-gp; ABCB1/MDR1) and ABCG2 (breast cancer resistance protein/mitoxantrone resistance protein) have emerged as key factors that regulate the intracellular concentrations of many small-molecule therapeutic inhibitors. Drug transporters may be overexpressed in cancer cells, reducing intracellular drug concentrations, and may allow the evolution of point mutations that confer stronger drug resistance. It is proposed that P-gp, a universally accepted biomarker of drug resistance, should also be considered as a molecular target in multidrug-resistant cancer. By exploiting the paradoxical hypersensitivity of multidrug-resistant cells, MDR1-inverse compounds can selectively eliminate cancer cells that overexpress P-gp. Successful targeting of multidrug-resistant cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors.

Original languageEnglish
Pages (from-to)246-252
Number of pages7
JournalCurrent Opinion in Drug Discovery and Development
Volume12
Issue number2
Publication statusPublished - Mar 1 2009

Keywords

  • ABC transporter
  • Chemotherapy
  • MDR1-inverse compound
  • Multidrug resistance
  • P-glycoprotein
  • Protein kinase inhibitor
  • Targeted therapy

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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