Recent developments in targeting carbonic anhydrase IX for cancer therapeutics

Paul C McDonald, Jean-Yves Winum, Claudiu T Supuran, Shoukat Dedhar, Paul C McDonald, Jean-Yves Winum, Claudiu T Supuran, Shoukat Dedhar

Abstract

Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme that is overexpressed by cancer cells from many tumor types, and is a component of the pH regulatory system invoked by these cells to combat the deleterious effects of a high rate of glycolytic metabolism. CAIX functions to help produce and maintain an intracellular pH (pHi) favorable for tumor cell growth and survival, while at the same time participating in the generation of an increasingly acidic extracellular space, facilitating tumor cell invasiveness. Pharmacologic interference of CAIX catalytic activity using monoclonal antibodies or CAIX-specific small molecule inhibitors, consequently disrupting pH regulation by cancer cells, has been shown recently to impair primary tumor growth and metastasis. Many of these agents are in preclinical or clinical development and constitute a novel, targeted strategy of cancer therapy.

Figures

Figure 1. Pharmacologic inhibition of CAIX activity…
Figure 1. Pharmacologic inhibition of CAIX activity inhibits cancer cell survival and invasion
Hypoxia induces a HIF-1-mediated signaling cascade that results nuclear translocation of HIF-1α and activation of hypoxia-regulated genes, including GLUT1, MCT1/4 and CAIX. Cells reprogram their metabolism to engage the glycoytic pathway, a “glycolytic switch” that results in increased production and export of lactate, leading to a decline in pHe. One consequence of extracellular acidification is the disruption of the intracellular pH (pHi), a decrease in which rapidly affects basic cellular functions. The overexpression of CAIX in hypoxia catalyzes the hydrolysis of CO2 to HCO3− and H+ in the extracellular microenvironment. The HCO3− is actively transported into the cancer cell, thereby regulating pHi and maintaining cell survival. The H+ participate in the generation of an increasingly acidic extracellular space, promoting tumor cell invasiveness. Inhibition of CAIX catalytic activity using monoclonal antibodies or specific small molecule inhibitors prevent the production of these enzymatic metabolites, leading to decreased survival and reduced invasive capacity.

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