Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 28, Issue 2, Pages 360-369Publisher
INFORMA HEALTHCARE
DOI: 10.3109/14756366.2012.736979
Keywords
Tumour cells; anoxia; acidification; pH; acetazolamide
Funding
- Medical Research Council (MRC)
- Cancer Research UK (CRUK)
- European Commission (EC FP7 METOXIA)
- MRC [G0500366] Funding Source: UKRI
- Cancer Research UK [11359] Funding Source: researchfish
- Medical Research Council [G0500366] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10163] Funding Source: researchfish
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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.
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