Despite microtubule-targeting agents (MTAs) being known as the most potent anti-cancer drugs, they exhibit several serious limitations, including an acquired resistance after initiation of MTA-based therapy. This, in turn, represents a driving force to develop novel therapeutic agents effectively targeting microtubules.
Activities of pyrrole-based carboxamides (PBCs) were examined against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. Cellular viability was assessed by MTS-based assay. Western blotting was used to examine cell cycle abnormalities (expression of cyclins A2, B1, Mdm2, pH3Ser10, etc.) and apoptotic markers (cleaved forms of caspase-3 and PARP). Cell cycle analysis was also examined by flow cytometry PI-based staining assay. Tubulin polymerization assay was used to examine PBC's ability to interfere with the microtubule's dynamical state.
We found that PBCs exhibit potent cytotoxic activities against H1299 lung cancer, PC-3 prostate cancer, HCC1806, and MDA-MD-231 breast cancer cells lines and induced their apoptotic death in a time- and dose-dependent manner. Cell cycle analysis revealed the accumulation of cancer cells in the G2/M phase after PBCs treatment. Importantly, selective enhancement of pH3(Ser10)-positive cells revealed PBC’s ability to induce selective accumulation of cancer cells in the M-phase. This was due to their ability to inhibit tubulin polymerization, thereby illustrating their molecular mechanism of action.
Our data describe the novel MTAs that interfere with the microtubule's dynamic state and thereby provide anti-proliferative and pro-apoptotic activities against a broad spectrum of epithelial cancer cell lines.
Legal entity responsible for the study
Russian Science Foundation (RSF) (grant no. 20-15-00001).
All authors have declared no conflicts of interest.