title: 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-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α 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 G2-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-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α 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-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Taiwan, PR China.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Cheng
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Lai
authors.forename: Kuang-Hsing
authors.initials: KH
authors.lastname: Shih
authors.forename: Chi-Yen
authors.initials: CY
authors.lastname: Chang
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Pan
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Tseng
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D012333:RNA, Messenger; D013449:Sulfonamides; D050257:Tubulin Modulators; C057812:indoline