Is resistance useless? Multidrug resistance and collateral sensitivity.
When cancer cells develop resistance to chemotherapeutics, it is frequently conferred by the ATP-dependent efflux pump P-glycoprotein (MDR1, P-gp, ABCB1). P-gp can efflux a wide range of cancer drugs; its expression confers cross-resistance, termed "multidrug resistance" (MDR), to a wide range of drugs. Strategies to overcome this resistance have been actively sought for more than 30 years, yet clinical solutions do not exist. A less understood aspect of MDR is the hypersensitivity of resistant cancer cells to other drugs, a phenomenon known as "collateral sensitivity" (CS). This review highlights the extent of this effect for the first time, and discusses hypotheses (e.g. generation of reactive oxygen species) to account for the underlying generality of this phenomenon, and proposes exploitation of CS as a strategy to improve response to chemotherapy.
Hall
Matthew D
MD
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Handley
Misty D
MD
Gottesman
Michael M
MM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species