Inhibition of V-ATPase and Carbonic Anhydrases as Interference Strategy with Tumor Acidification Processes

Mario      Perez-Sayans; Abel      Garcia-Garcia; Andrea      Scozzafava; Claudiu      T. Supuran

Abstract

Two of the key proteins involved in tumor acidification are the V-ATPase and the tumor-associated carbonic anhydrases (CAs), such as CA IX and XII. Although there are many chemical classes of V-ATPase inhibitors, most of them are toxic for mammals and their potential use as antitumor drugs is limited. The proton pump inhibitors (PPIs), a class of antiulcer agents in clinical use for more than 30 years, have been proven to be useful in modulating tumor acidification, presumably by inactivating V-ATPase, through modification of Cys residues essential for the catalytic activity of the ATPase. This mechanism of action has yet to be demonstrated, but several recent clinical trials showed the efficacity of this approach for inhibiting the growth of tumors and their re-sensitivization to anticancer drugs such as cisplatin, or doxorubicin. Further studies are anyhow warranted to better understand the role of PPIs in the management of cancer. The monoclonal antibodies (mAbs) girentuximab, and its 124I -radiolabelled variant targeting CA IX are in advanced clinical trials both for the treatment and imaging of hypoxic tumors overexpressing CA IX. Small molecule CA IX inhibitors, of sulfonamide and coumarin type are in advanced preclinical evaluation, both for imaging and treatment of solid tumors and metastases in which CA IX/XII are present. As cancer is still a big clinical problem and most of the hypoxic tumors do not respond to classical anticancer drugs or to radiotherapy, the development of alternative anticancer approaches, such as interference with tumor acidification through inhibition of VATPase and CAs, represents an interesting avenue for future research.

Keywords: Anticancer drug, V-ATP-ase, carvonic anhydrase, proton pump inhibitor, omeprazole, sulfonamide, coumarin, tumor pH, tumor acidification, radiotherapy