Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

Abstract

Human carbonic anhydrase (CA) IX is a tumor-associated protein, since it is scarcely present in normal tissues, but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. Due to these features, the characterization of its biochemical, structural, and functional features for drug design purposes has been extensively carried out, with consequent development of several highly selective small molecule inhibitors and monoclonal antibodies to be used for different purposes. Aim of this review is to provide a comprehensive state-of-the-art of studies performed on this enzyme, regarding structural, functional, and biomedical aspects, as well as the development of molecules with diagnostic and therapeutic applications for cancer treatment. A brief description of additional pharmacologic applications for CA IX inhibition in other diseases, such as arthritis and ischemia, is also provided.

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

“…However, to prevent intracellular H þ accumulation cancer cells upregulates proton exchangers that extrude protons in excess contributing to acidify extracellular tumour microenvironment 9,11,12 . Among these proton exchangers, a primary role is played by CA IX, an enzyme overexpressed in many types of cancers, including prostate cancer, with the potential to represent both a promising tumour biomarker and a specific target for future cancer therapies 13,[30][31][32][33][37][38][39][40][41]44 . Under the pressure of the acidic microenvironment, CA IX expression and activity are upregulated in both tumour cells 30,44 and the exosomes released extracellularly 30 .…”

“…Furthermore, CA IX has been validated as a target of new therapies against hypoxic tumours with one sulphonamide inhibitor (SLC-0111) in Phase Ib/II clinical trials 13,30,37-39(p20), [40][41][42] . Indeed CA IX is the most widely expressed gene in response to hypoxia, playing a pivotal role in tumour pH regulation 13,30,37,41 ; thus conferring to cancer cells a survival advantage in hypoxic and acidic microenvironments 43 . Thus, it is clear that the acidic microenvironment induces the up-regulation of the CA IX expression and activity in both tumour cells 30,44 and tumour released exosomes 30 .…”

Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents

“…Among all, the hCA isoforms IX and XII are overexpressed in many of cancer types as these are tumor-associated transmembrane bound enzymes, mainly hypoxic tumors, which are regarded as emerging potential targets for various tumor types [43]. The overexpression of hCA isoforms IX and XII further contributes to the tumor progression, angiogenesis, metastasis, and proliferation of a variety of tumor cells [44]. In order to exhibit potential cytotoxicity without adverse effects, an anticancer agent should selectively inhibit tumor-associated hCAs IX and XII over other hCAs.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…The membrane bound carbonic anhydrase isoforms hCA IX and hCA XII are considered as therapeutic targets for hypoxic tumors as both of these enzymes are associated with cancer progression, metastasis, and impaired therapeutic response. The development of new and effective inhibitors is driven by the specific targeting of hCA IX / hCA XII over the ubiquitous cytosolic offtarget isoforms hCA I and hCA II [33]. Bua and colleagues investigated a new cyclic ureidosulfonamide chemotype based on a 2H-benzo[e] [1,2,4]thiadiazin-3(4H)-one 1,1-dioxide scaffold, and resulting from the combination design of the structure of saccharin and acesulfame K [2].…”