Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit?

Abstract

Enhanced drug extrusion from cells due to the overexpression of the ATP-binding cassette (ABC) drug transporters inhibits the cytotoxic effects of structurally diverse and mechanistically unrelated anticancer agents and is a major cause of multidrug resistance (MDR) of human malignancies. Multiple compounds can suppress the activity of these efflux transporters and sensitize resistant tumor cells, but despite promising preclinical and early clinical data, they have yet to find a role in oncologic practice. Based on the knowledge of the structure, function, and distribution of MDR-related ABC transporters and the results of their preclinical and clinical evaluation, we discuss probable reasons why these inhibitors have not improved the outcome of therapy for cancer patients. We also outline new MDR-reversing strategies that directly target ABC transporters or circumvent relevant signaling pathways.

• Authors: Man Yu, Alberto Ocana, Ian F Tannock
• Journal: Cancer metastasis reviews (Cancer Metastasis Rev) Vol. 32 Issue 1-2 Pg. 211-27 (Jun 2013) ISSN: 1573-7233 [Electronic] Netherlands
• PMID: 23093326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents

Topics

• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Humans
• Neoplasms (drug therapy, genetics, metabolism)
• Treatment Failure