Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer
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).
References (41)
- et al.
Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy
Eur J Cancer
(2004) - et al.
Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells
Lung Cancer
(2005) - et al.
Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump
Blood
(2004) - et al.
Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (−/−) mice
Drug Metab Dispos
(2005) - et al.
Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel
Clin Cancer Res
(2002) - et al.
The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models
Br J Cancer
(2003) - et al.
Redox regulation of P-glycoprotein-mediated multidrug resistance in multicellular prostate tumor spheroids
Int J Cancer
(2000) - et al.
Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576
Clin Cancer Res
(2003) - et al.
P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats
Cancer Chemother Pharmacol
(2005) - et al.
Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells
Int J Cancer
(2006)