Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro

Gieling, Roben, Parker, Catriona A., De Costa, Lisa A., Robertson, Naomi, Harris, Adrian L., Stratford, Ian J. and Williams, Kaye J. (2013) Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro. Journal of Enzyme Inhibition and Medicinal Chemistry, 28 (2). pp. 360-369. ISSN 1475-6366

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Official URL: http://dx.doi.org/10.3109/14756366.2012.736979

Abstract

Carbonic anhydrase IX (CA IX) is a hypoxia-regulated enzyme, overexpressed in many types of human cancer. CA IX is involved in pH homeostasis, contributing to extracellular acidification and tumourigenesis. Acidification of the extracellular milieu can impact upon cellular uptake of chemotherapeutic drugs by favouring weak acids (e.g. melphalan), but limiting access of weak bases (e.g. doxorubicin). We investigated whether alterations of CA IX activity affected anti-cancer drug uptake and toxicity. CA inhibitor acetazolamide (AZM) enhanced doxorubicin toxicity but reduced melphalan toxicity in cell lines that highly expressed CA IX under anoxic conditions (HT29 and MDA435 CA9/18). The toxicity changes reflected modification of passive drug uptake. AZM did not alter toxicity or uptake in cells with low CA IX activity (HCT116 and MDA435 EV1). AZM lowered intracellular pH in HT29 and MDA435 CA9/18 cells under anoxic conditions. CA IX activity has chemomodulatory properties and is an attractive target for anti-cancer therapy.

Item Type: Article
Uncontrolled Keywords: Tumour cells, anoxia, acidification, pH, acetazolamide
Subjects: A300 Clinical Medicine
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Paul Burns
Date Deposited: 13 Jul 2018 13:16
Last Modified: 13 Jul 2018 13:16
URI: http://nrl.northumbria.ac.uk/id/eprint/34990

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