Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors.

Claudiu T Supuran

doi:10.3390/metabo7030048

Abstract

Hypoxia and acidosis are salient features of many tumors, leading to a completely different metabolism compared to normal cells. Two of the simplest metabolic products, protons and bicarbonate, are generated by the catalytic activity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), with at least two of its isoforms, CA IX and XII, mainly present in hypoxic tumors. Inhibition of tumor-associated CAs leads to an impaired growth of the primary tumors, metastases and reduces the population of cancer stem cells, leading thus to a complex and beneficial anticancer action for this class of enzyme inhibitors. In this review, I will present the state of the art on the development of CA inhibitors (CAIs) targeting the tumor-associated CA isoforms, which may have applications for the treatment and imaging of cancers expressing them. Small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials, and antibodies (girentuximab, discontinued in Phase III clinical trials) will be discussed, together with the various approaches used to design anticancer agents with a new mechanism of action based on interference with these crucial metabolites, protons and bicarbonate.

Highlights

A salient feature of many tumors is the fact that they are hypoxic and acidic compared to normal tissues of the same type
In hypoxia, which as mentioned above is frequent in many tumor cells [1,2,3], an accumulation of HIF-1α occurs, followed by its translocation from the cytosol to the nucleus, where it forms a dimer with a constitutive subunit, HIF-1β, leading to an active transcription factor, which, by interaction with a hypoxia responsive element (HRE) found on different genes, leads to overexpression of proteins involved in aerobic glycolysis
This study showed that CA IX is one of the metabolic components of the cellular migration and invasion mechanisms in hypoxic tumors, and provides new mechanistic insights into the role played by this enzyme in tumor cell biology, with the possibility to design dual agents, targeting both these enzymes (CA IX and matrix metalloproteinase 14 (MMP14)) as new antitumor drugs [50]

Summary

Introduction

A salient feature of many tumors is the fact that they are hypoxic and acidic compared to normal tissues of the same type. In hypoxia,ofwhich mentioned above is effects frequent tumor cells [1,2,3],cells, an The overexpression these as proteins has profound on in themany metabolism of cancer accumulation of HIF-1α occurs, followed by its translocation from the cytosol to the nucleus, where which on one hand are deprived of oxygen for the normal metabolism involving the oxidative itphosphorylation forms a dimer with a constitutive. ExportThus, protons in exchange pathway, the glycolytic one, occurs, with the formation of pyruvic (and lactic acids) from glucose, which generates less ATP (compared to the oxidative pathway), but which seems to be enough for the cancer cells to survive in hypoxic conditions [1,2,3,4]. Subsequently metastasis of the primary tumors [12,13,14,15]

Proteins involved in pH regulation in tumors

Structure

Anti-CA IX Antibodies

Anti-CA XII Antibodies

Conclusions