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

Abstract

Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1a (HIF-1a) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1a mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-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 IC 50 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 IC 50 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 VEGFinduced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1a protein but also destabilized HIF-1a mRNA. The mechanism of causing unstable of HIF-1a mRNA by MPT0B098 is through decreasing RNAbinding 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-1a of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies. Mol Cancer Ther; 12(7); 1202-12. Ó2013 AACR.

The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation

“…Furthermore some studies pointed out that some TBAs are endowed with the ability to reduce HIF-1α upon treatment2021. In this context we evaluated the effects of TR-764, compared to CA-4, on the regulation of hypoxic stimuli.…”

“…It is well known that intratumor hypoxia is associated with cellular resistance to chemotherapy, due to overactivation of HIFs. Furthermore some studies pointed out that some TBAs are endowed with the ability to reduce HIF-1α upon treatment 20 21 . In this context we evaluated the effects of TR-764, compared to CA-4, on the regulation of hypoxic stimuli.…”

HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions

“…In our studies, HDAC6 inhibition by HDAC6 inhibitors or siRNA knockdown resulted in reduced caspase 3 activation. It has been reported that microtubule disruption leads to increased apoptotic signaling and caspase activation [34, 35]. α-tubulin is a endogenous substrate of HDAC6 [10, 11, 36–38].…”

Post-transcriptional regulation of cytokine and growth factor signaling in cancer

“…In hypoxic conditions, cytoplasmic localization and ARE-binding activity of ELAVL1 increases, leading to expression of pro-angiogenic mRNAs, likely due to activation of ELAVL1 by PKC and other kinases [73–77]. Moreover, ELAVL1 promotes chemo-resistance by binding to and stabilizing HIF1a and other hypoxia-associated mRNAs [78–80]. Interestingly, the mTOR inhibitor, rapamycin, inhibits ELAVL1 phosphorylation by PKC and decreases VEGF mRNA stability, suggesting that rapamycin might inhibit production of VEGF through its effect on ELAVL1, and thereby prevents neoplastic angiogenesis [81].…”