cvt-313 and Breast-Neoplasms

The 26S proteasome plays important roles in many intracellular processes and is therefore a critical intracellular cellular target for anticancer treatments. The primary aim of the current study was to identify critical proteins that may play roles in opposing the antisurvival effect of the proteasome inhibitor bortezomib together with the calcium-chelator BAPTA-AM in cancer cells using label-free LC-MS/MS. In addition, based on the results of the proteomic technique, a novel and more effective inhibitor combination involving bortezomib as well as OTSSP167 was developed for breast cancer cells.. Using label-free LC-MS/MS, it was found that expressions of 1266 proteins were significantly changed between the experimental groups. Among these proteins were cell division cycle 5-like (Cdc5L) and drebrin-like (DBNL). We then hypothesized that inhibition of the activities of these two proteins may lead to more effective anticancer inhibitor combinations in the presence of proteasomal inhibition. In fact, as presented in the current study, Cdc5L phosphorylation inhibitor CVT-313 and DBNL phosphorylation inhibitor OTSSP167 were highly cytotoxic in 4T1 breast cancer cells and their IC. Altogether, the results presented here indicate that bortezomib + OTSSP167 is a novel and effective combination and may be tested further for cancer treatment in vivo and in clinical settings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Female; Humans; Inhibitory Concentration 50; Naphthyridines; Phosphorylation; Proteomics; Purines; RNA-Binding Proteins; Spheroids, Cellular; Staining and Labeling