Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy

Abstract

Resistance to cancer chemotherapy involves both altered drug activity at the designated target and modified intra-tumour pharmacokinetic properties (e.g. uptake, metabolism). The membrane transporter P-glycoprotein (P-gp) plays a major role in pharmacokinetic resistance by preventing sufficient intracellular accumulation of several anticancer agents. Whilst inhibiting P-gp has great potential to restore chemotherapeutic effectiveness in blood-borne cancers, the situation in solid tumours is less clear. Therefore, the degree of resistance tumours pose to the cytotoxicity of vinblastine and doxorubicin was characterised using the multicellular tumour spheroid model. Tumour spheroids were generated from either drug-sensitive MCF7WT breast cancer cells or a resistant P-gp-expressing variant (NCI/ADRRes). Drug-induced cytotoxicity in tumour spheroids was measured using an outgrowth assay and compared with that observed in monolayer cultures. As anticipated, the 3-D organisation of MCF7WT in tumour spheroids was associated with a reduction in the potency of doxorubicin and vinblastine—i.e. the inherent multicellular resistance phenomenon. In contrast, tumour spheroids from NCI/ADRRes cells did not display multicellular resistance. However their constitutive expression of P-gp reduced the potency of both anticancer drugs. Moreover, the highly potent P-gp inhibitor, the anthranilic acid derivative, XR9576, was able to restore the cytotoxic efficacy of both drugs in tumour spheroids comprising NCI/ADRRes cells. The results suggest that inhibition of P-gp in solid tumours is achievable and that generation of potent inhibitors will provide a significant benefit towards restoration of chemotherapy in solid tissues.