Is resistance useless? Multidrug resistance and collateral sensitivity - PubMed (original) (raw)

Review

Is resistance useless? Multidrug resistance and collateral sensitivity

Matthew D Hall et al. Trends Pharmacol Sci. 2009 Oct.

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.

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Figures

Figure 1

Figure 1

The efflux cycle of P-gp described in Box 1.

Figure 2

Figure 2

Collateral sensitivity defined schematically. (a) Representative dose-response curve of a parental cell line (solid line, center). Development of resistance to a drug, and concomitant cross-resistance to a variety of cytotoxic agents conferred by ABC transporters such as P-gp, results in a loss of sensitivity of possibly several orders of magnitude (dotted line, right). Inhibitors of P-gp (so-called reversal agents) inhibit the efflux function of P-gp, restoring cellular accumulation and re-sensitizing cross-resistant cells to levels approaching that of the original parental cells. A small number of agents have been demonstrated to sensitize multidrug-resistant cells to a greater degree than the original parental cells (dashed line, left). This property is termed collateral sensitivity (CS). (b) The determination of collateral sensitivity (≤0.5) and multidrug resistance (≥2) as defined in this review. It is important to emphasize that a lack of cross-resistance to an agent—the same drug response for a parental and resistant line—is not collateral sensitivity, but merely a lack of resistance. This occurs, for example, with the P-gp substrate vinblastine against cisplatin-resistant 7407-CP human liver carcinoma cells which do not express P-gp as part of their resistance phenotype [112].

Figure 3

Figure 3

Structures of compounds described in the text.

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References

    1. Luo J, et al. Principles of Cancer Therapy: Oncogene and Non-Oncogene Addiction. Cell. 2009;136:823–837. - PMC - PubMed
    1. Gottesman MM. Mechanisms of Cancer Drug Resistance. Annu Rev Med. 2002;53:615–627. - PubMed
    1. Szakacs G, et al. Targeting Multidrug Resistance in Cancer. Nat Rev Drug Discov. 2006;5:219–234. - PubMed
    1. Sheps JA, Ling V. Preface: The Concept and Consequences of Multidrug Resistance. Pflugers Arch - Eur J Physiol. 2007;453:545–553. - PubMed
    1. Szybalski W, Bryson V. Genetic Studies on Microbial Cross Resistance to Toxic Agents. I Cross Resistance of Escherichia Coli to Fifteen Antibiotics. J Bacteriol. 1952;64:489–499. - PMC - PubMed

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