u-104 and Triple-Negative-Breast-Neoplasms

Conventional chemotherapy represents the main systemic treatment used for triple-negative breast cancer (TNBC) patients, although many of them develop drug resistance. The hypoxic TME is the crucial driver in the onset of insensitivity to chemotherapy. In this research, we elucidated the role played by bone marrow-derived mesenchymal stem cells (BM-MSCs) in reducing cisplatin effects in TNBC. BT-549 and MDA-MB-231 cells, grown under hypoxic conditions in the presence of conditioned medium obtained from BM-MSCs (CM-MSCs), showed a strong cisplatin insensitivity and increased expression levels of carbonic anhydrase IX (CA IX). Therefore, we inhibited CM-MSC-induced CA IX by SLC-0111 to potentiate chemotherapy efficacy in TNBC cells. Our results showed that CM-MSCs under hypoxic conditions caused an increase in the ability of TNBC cells to form vascular structures, migrate and invade Matrigel. Cell treatment with cisplatin plus SLC-0111 was able to block these mechanisms, as well as the signaling pathways underlying them, such as p-AKT, p-ERK, CD44, MMP-2, vimentin, β-catenin, and N-cadherin, more effectively than treatment with single agents. In addition, a significant enhancement of apoptosis assessed by annexin V, caspase-3 expression and activity was also shown. Taken together, our results demonstrated the possibility, through CA IX inhibition, of returning TNBC cells to a more chemosensitive state.

Topics: Bone Marrow; Carbonic Anhydrase IX; Cisplatin; Humans; Mesenchymal Stem Cells; Triple Negative Breast Neoplasms

Carbonic anhydrase IX (CAIX) is considered a target for therapeutic intervention in solid tumors. In this study, the efficacy of the inhibitor, 4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)benzenesulfonamide (SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149 is a better inhibitor than acetazolamide against CAIX. Binding of SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic and CAII explain binding preferences. In cell culture, SLC-149 is a more effective inhibitor of CAIX activity in a triple-negative breast cancer cell line than previously studied sulfonamide inhibitors. SLC-149 is also a better inhibitor of activity in cells expressing CAIX versus CAXII. However, SLC-149 has little effect on cytotoxicity, and high concentrations are required to inhibit cell growth, migration, and invasion. These data support the hypothesis that CAIX activity, shown to be important in regulating extracellular pH, does not underlie its ability to control cell growth.

Topics: Antineoplastic Agents; Breast Neoplasms; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Humans; Hydrogen-Ion Concentration; Models, Molecular; Triple Negative Breast Neoplasms