Carbonic Anhydrase Inhibitors and the Management of Cancer

Abstract

Recent progress in understanding the role of catalytically active carbonic anhydrases in tumors has opened new possibilities for diagnostic and/or therapeutic applications of carbonic anhydrase inhibitors selectively blocking the enzyme activity of cancer-related isoforms, namely CA IX and CA XII. Different classes of inhibitors have been investigated in order to evaluate their usefulness as in vivo imaging tools, as modulators of intratumoral pH that influences uptake of conventional chemotherapeutics, or as drugs impeding survival of tumor cells exposed to physiological stresses including hypoxia and acidosis. Here we summarize the most important data related to expression, regulation and functional aspects of cancer-related carbonic anhydrases and discuss advances in synthesis and preclinical studies of isozyme-selective and highly efficient carbonic anhydrase inhibitors.

CD147 subunit of lactate/H+symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

“…We hypothesized that carbonic anhydrase IX (CAIX) and the H + /lactate symporter MCT4, induced by HIF-1, should be considered as two prominent candidates for pHi regulation and promising targets for anticancer strategies (8). The first target, CAIX, characterized by a very restricted pattern of tissue expression, is hijacked in many malignancies (37), and recent work from several groups has validated the hypothesis whereby CAIX controls pHi by accelerating H + extrusion and promoting tumor growth (19,38) and metastasis (39). For the second target, we recently demonstrated by monitoring tumor pHi in vivo by 31 P-NMR spectrometry that tumors expressing MCT4 had a more alkaline pHi and lower external pH (pHe) than tumors expressing MCT1/2 only (40).…”

Selective Inhibition of Carbonic Anhydrase IX Decreases Cell Proliferation and Induces Ceramide-Mediated Apoptosis in Human Cancer Cells

“…Supuran, 2008). CA IX has been shown to be upregulated in a number of human cancer tissues as a consequence of either hypoxia-induced or constitutive hypoxiainducible factor-1 activation, whereas it is not expressed in their normal counterparts, except for gastric mucosa (Robertson et al, 2004;Pastorekova et al, 2007). Although these characteristics make CA IX an interesting target for novel approaches in anticancer therapy, the exact role of CA IX in tumor growth and progression is still unknown.…”

“…Low extracellular pH seems to provide a selective advantage for tumor growth and development in human tumors (Vaupel et al, 1990). On the contrary, intracellular acidosis poses a threat to cell survival; therefore, maintenance of a normal pH i is a key cellular strategy to protect against apoptotic death and permit tumor cell proliferation (Pastorekova et al, 2007;Swietach et al, 2007). Recent experimental evidence has demonstrated the pivotal role of CAs in keeping pH i alkaline (Swietach et 2009).…”

“…Indeed, there are cytosolic, mitochondrial, secreted, and membrane-bound isozymes (Pastorekova et al, 2004). Among the latter, CA IX and CA XII have been found to be overexpressed in a wide variety of human tumors and involved in cancer aggressiveness and progression (Robertson et al, 2004;Pastorekova et al, 2007). Recent studies have revealed that CAIX is a downstream gene either induced by hypoxia through activation of hypoxia-inducible factor-1 (Wykoff et al, 2000) or constitutively expressed in von Hippel-Lindau (VHL)-defective cells (Gnarra et al, 1994).…”

Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy

“…They are zinc metalloenzymes that catalyse the reversible interconversion of carbon dioxide and bicarbonate and thereby regulate physiological pH and other processes. At least two of them, CAs IX and XII (CAIX and CAXII), are expressed in a wide variety of malignancies and implicated in tumour growth (see details in reference Pastorekova et al, 2007). CAIX in particular is linked to poor prognosis in a number of human tumours.…”