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

Roben G. Gieling, Catriona A. Parker, Lisa A. De Costa, Naomi Robertson, Adrian L. Harris, Ian J. Stratford, Kaye J. Williams

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)360-369
Number of pages10
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume28
Issue number2
Early online date19 Nov 2012
DOIs
Publication statusPublished - 1 Apr 2013

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