| Abstract: | In recent years, epigenetic therapeutics is a new generation of chemotherapeutics for cancer. Microtubule-targeted agents constitute a type of anticancer drugs largely used in the clinics. Cells generate distinct microtubule subtypes through expression of different iso-types and through post-translational modifications, including acetylation, detyrosination, polyglutamination and polyglycylation. The acetylation of α-tubulin K-40 is controlled by the balance between acetyltransferase and de-acetylase expression. MEC-17, one of α-tubulin acetyltransferases, plays an important role in the regulation of acetylation of α-tubulin. Through screening of compounds that is able to selectively acetylate α-tubulin, MPT0B292 was identified.Our results show that MPT0B292 up-regulate MEC-17 gene and protein expression, which subsequently lead to enhancing α-tubulin acetylation. MPT0B292 exhibits potent anti-proliferative activities toward various human cancer cells with IC50 ranged from 75 to 200 nM. In addition, HUVEC and WI-38 cells were much less susceptibility to the anti-proliferative effect of MPT0B292 with IC50 4 and12 μM, respectively. In FACS analysis of cell cycle, MPT0B292 induces G2/M phase arrest with concomitantly losses from G0/G1 and S phases in a concentration-dependent manner. Furthermore, MPT0B292 induces ROS generation in a concentration-dependent manner by FACS analysis, which leads to damaging mitochondria and triggering cell apoptosis. The effects MPT0B292-induced ROS and cell apoptosis could be significantly rescued by pretreatment with N-acetylcysteine, Diphenyleneiodonium (DPI) and rotenone. Moreover, the amount of ROS induced by MPT0B292 was significantly reduced by knockdown of MEC-17 with siRNA and resulted in rescuing cell viability. In addition, MPT0B292 inhibits cell motility by an increase in cellular focal adhesion area. Moreover, MPT0B292 shows potent activity against the growth of xenograft tumor of lung cancer cell, A549, without significantly compromising the mice body weight. MPT0B292 also decreases lung metastasis in orthotopical breast cancer model. These data indicate MPT0B292 is a promising anticancer compound with unique action of mechanism that has potential for future development. |
