Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness

Abstract

Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation.

Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness

“…It is known that CA-IX is expressed ectopically by almost all tumors, especially in the advanced stages [30]. The inhibition potential of two sulphonamide compounds, SLC-0111 and AA-06-05, has been initially evaluated in survival/proliferation experiments.…”

“…The reduction of E-Cadherin determines the loss of cell-cell adhesion, allowing cell migration. This process, together with the acidification of pHe, which improves the action of metalloproteases on extracellular matrix (ECM) proteolysis, enhances the metastatic potential of cancer cells [30]. Both tumor cells used in this study are characterized by a high metastatic potential [34,35].…”

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

“…CAIX is commonly overexpressed in cancer cells due to the hypoxic conditions that pervade growing tumors. CAIX has shown to be a mediator of tumor proliferation and metastasis [43]. This led us to consider the pan carbonic anhydrase inhibitor, AZ, as a viable therapeutic.…”

Carbonic anhydrases in human keratinocytes and their regulation by all‐trans retinoic acid and 1α,25‐dihydroxyvitamin D3

“…An immunohistochemistry analysis showed the expression of CAIX and CAXII in various epithelial components of the skin, hair follicles, sebaceous glands and basal parts of epidermis . CAIX and CAXII are also highly expressed in epidermal tumors but not in melanocytic tumors …”