A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity

Abstract

Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk between cancer and stromal cells and the interactions with the extracellular matrix, hypoxia and acidosis contribute to trigger a new tumor cell identity and to enhance tumor heterogeneity and metastatic spread. In highly aggressive triple-negative breast cancer, tumor cells show a significant capability to change their phenotype under the pressure of the hypoxic microenvironment. In this study, we investigated whether targeting the hypoxia-induced protein carbonic anhydrase IX (CA IX) could reduce triple-negative breast cancer (TNBC) cell phenotypic switching involved in processes associated with poor prognosis such as vascular mimicry (VM) and cancer stem cells (CSCs). The treatment of two TNBC cell lines (BT-549 and MDA-MB-231) with a specific CA IX siRNA or with a novel inhibitor of carbonic anhydrases (RC44) severely impaired their ability to form a vascular-like network and mammospheres and reduced their metastatic potential. In addition, the RC44 inhibitor was able to hamper the signal pathways involved in triggering VM and CSC formation. These results demonstrate that targeting hypoxia-induced cell plasticity through CA IX inhibition could be a new opportunity to selectively reduce VM and CSCs, thus improving the efficiency of existing therapies in TNBC.

Regulation of cancer stem cells in triple negative breast cancer

“…Carbonic anhydrase CAIX is another hypoxia-induced factor directly regulated by HIF allowing cancer cells to regulate intracellular pH during hypoxia [138] . It is highly expressed in TNBC where it correlates with poor survival and metastases as well as promotes TNBCSC survival and stemness [138][139][140] .…”

Identification and characterization of a new potent inhibitor targeting CtBP1/BARS in melanoma cells

“…Speci cally, SLC-0111 inhibits the enzymatic activity of CAIX, an enzyme that, catalyzing the conversion of carbon dioxide into carbonic acid, controls the intracellular and extracellular pH. Hypoxia condition induces the expression of CAIX, which, in turn, contributes to the acidi cation of the extracellular milieu and promotes the acquisition of tumor malignancy [100,103]. Treatment with 100 µM of SLC-0111 for 72 hours affects the viability of the high-malignant acid cancer subpopulation particularly addicted to CAIX activity, i.e., the cells growing under speci c conditions of acidosis within the tumor mass of the breast, melanoma and colorectal tumors.…”

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…Furthermore, the RC44 inhibitor was found to be effective in the inhibition of the signal pathways involved in the VM and CSC development. Based on these findings, it appears that targeting hypoxia-induced cell plasticity with CAIX inhibition may provide a novel option to selectively diminish VM and CSCs in TNBC, hence increasing the efficacy of currently available therapies 132 .…”