Dataset Information

Is resistance useless? Multidrug resistance and collateral sensitivity.

ABSTRACT: 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.

SUBMITTER: Hall MD

PROVIDER: S-EPMC2774243 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Is resistance useless? Multidrug resistance and collateral sensitivity.

Hall Matthew D MD Handley Misty D MD Gottesman Michael M MM

Trends in pharmacological sciences 20090915 10

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 ...[more]

PMID: 19762091

Similar Datasets

Project description:Polymorphisms in the Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene and the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene alter the malaria parasite's susceptibility to most of the current antimalarial drugs. However, the precise mechanisms by which PfMDR1 contributes to multidrug resistance have not yet been fully elucidated, nor is it understood why polymorphisms in pfmdr1 and pfcrt that cause chloroquine resistance simultaneously increase the parasite's susceptibility to lumefantrine and mefloquine-a phenomenon known as collateral drug sensitivity. Here, we present a robust expression system for PfMDR1 in Xenopus oocytes that enables direct and high-resolution biochemical characterizations of the protein. We show that wild-type PfMDR1 transports diverse pharmacons, including lumefantrine, mefloquine, dihydroartemisinin, piperaquine, amodiaquine, methylene blue, and chloroquine (but not the antiviral drug amantadine). Field-derived mutant isoforms of PfMDR1 differ from the wild-type protein, and each other, in their capacities to transport these drugs, indicating that PfMDR1-induced changes in the distribution of drugs between the parasite's digestive vacuole (DV) and the cytosol are a key driver of both antimalarial resistance and the variability between multidrug resistance phenotypes. Of note, the PfMDR1 isoforms prevalent in chloroquine-resistant isolates exhibit reduced capacities for chloroquine, lumefantrine, and mefloquine transport. We observe the opposite relationship between chloroquine resistance-conferring mutations in PfCRT and drug transport activity. Using our established assays for characterizing PfCRT in the Xenopus oocyte system and in live parasite assays, we demonstrate that these PfCRT isoforms transport all 3 drugs, whereas wild-type PfCRT does not. We present a mechanistic model for collateral drug sensitivity in which mutant isoforms of PfMDR1 and PfCRT cause chloroquine, lumefantrine, and mefloquine to remain in the cytosol instead of sequestering within the DV. This change in drug distribution increases the access of lumefantrine and mefloquine to their primary targets (thought to be located outside of the DV), while simultaneously decreasing chloroquine's access to its target within the DV. The mechanistic insights presented here provide a basis for developing approaches that extend the useful life span of antimalarials by exploiting the opposing selection forces they exert upon PfCRT and PfMDR1.

Dataset Information

Is resistance useless? Multidrug resistance and collateral sensitivity.

Publications

Is resistance useless? Multidrug resistance and collateral sensitivity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets