MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1 alpha mRNA through Decreasing Nuclear-Cytoplasmic Translocation of RNA-Binding Protein HuR

作者：Cheng Yun Ching; Liou Jing Ping; Kuo Ching Chuan; Lai Wen Yang; Shih Kuang Hsing; Chang Chi Yen; Pan Wen Yu; Tseng Joseph T; Chang Jang Yang^*

来源：Molecular Cancer Therapeutics, 2013, 12(7): 1202-1212.

DOI：10.1158/1535-7163.MCT-12-0778

Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1 alpha(HIF-1 alpha) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1 alpha mRNA. We recently discovered a novel indoline-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 the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G(2)-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1 alpha protein but also destabilized HIF-1 alpha mRNA. The mechanism of causing unstable of HIF-1 alpha mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1 alpha of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.

• 出版日期2013-7