Abstract 4461: MPT0B098, a novel microtubule inhibitor, displays potent anti-angiogenic activity via destabilizing hypoxia-inducible factor-1alpha mRNA

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Identification of a single agent that is able to target tumor cells, rapidly destroy tumor vasculature and inhibit angiogenesis could be an ideal approach for targeting solid tumors. We recently discover a novel sulfonamide compound, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine binding site of tubulin. MPT0B098 is active against various human cancer cell growth with IC50 values ranged from 70-300 nM. Notably, HUVEC cells exhibit less susceptibility to the inhibitory effect of MPT0B098 with an IC50 of 510 nM. In addition, MPT0B098 exhibits no cross resistance with vincristine, paclitaxel, etoposide and camptothecin-resistant cell lines. Interestingly, MPT0B098 is still active toward cells (KB L30) with beta1-tubulin mutation. MPT0B098 arrests cells in G2/M phase and subsequently induces cell apoptosis through the caspase-dependent apoptotic pathway. In addition, using sub-lethal dose, MPT0B098 effectively suppressed to the tube formation and migration of HUVECs induced by VEGF. The expression levels of HIF-1alpha and VEGF were significantly inhibited in a concentration-dependent manner by MPT0B098 under hypoxic condition. Furthermore, HIF-1alpha-regulated genes, including cathepsin D, PDGF, VEGF, and VHL, were found to be down-regulated by MPT0B098 in A549 cells. Moreover, the decrease of the amount of HuR, a HIF-1alpha mRNA stability protein, translocated from nuclear to cytoplasm and suppression of AKT activity were coincided with decreased amount of HIF-1alpha mRNA by MPT0B098 treatment under hypoxia condition. MPT0B098 significantly suppressed tumor growth and microvessel density of tumor in H460 and KB-Vin10 xenografted mouse model. Taken together, our results indicate that MPT0B098 is a promising anticancer drug with potential for the treatment of human malignancies. (The study was supported by grants of DOH99-TD-C-111-004 from Department of Health and CA-099-PP-02 from National Health Research Institutes, Taiwan, R.O.C.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4461. doi:10.1158/1538-7445.AM2011-4461