Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer

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Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitise cancers?

Section snippets

Introduction: the importance of multidrug efflux pumps in cancer

Drug resistance in cancer comprises a network of contributing cellular and tissue factors. The phenotype denoted as multidrug resistance (MDR) is characterised by the contribution of drug efflux pumps such as P-glycoprotein (P-gp). P-gp confers resistance by preventing sufficient accumulation of anticancer drugs within cells. The presence of multidrug efflux pumps in various types of cancer has been widely demonstrated. Often this expression is observed before chemotherapy and reflects the

Pharmacological approaches

The design of P-gp inhibitors has received the greatest attention thus far and has progressed through three distinct generations. In comparison with the first, the second generation P-gp inhibitors were more potent, although they displayed unwanted and toxic pharmacokinetic properties. Third generation inhibitors have been produced by combinatorial chemistry and from studying structure–activity relationships. Their advantages include high in vitro potency and improved selectivity, factors that

Conclusions

The past 30 years of investigation with multidrug efflux pumps have altered many aspects of our understanding of membrane transport processes. Attempts to circumvent their role in conferring a resistant phenotype have also facilitated changes to the design of clinical trials and drug development. One constant throughout this period has been the value of providing increased basic biochemical and pharmacological understanding to facilitate better characterisation and treatment of clinical

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research was funded by a Cancer Research UK Program grant (SP1861/0401).

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