Molecular mechanisms of the antitumor activity of SB225002: a novel microtubule inhibitor

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dc.contributor.authorA E Goda-
dc.contributor.authorM Koyama-
dc.contributor.authorY Sowa-
dc.contributor.authorK M Elokely-
dc.contributor.authorT Yoshida-
dc.contributor.authorBo Yeon Kim-
dc.contributor.authorT Sakai-
dc.date.accessioned2017-04-19T09:41:37Z-
dc.date.available2017-04-19T09:41:37Z-
dc.date.issued2013-
dc.identifier.issn0006-2952-
dc.identifier.uri10.1016/j.bcp.2013.04.011ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/11435-
dc.description.abstractSB225002 (SB) is an IL-8 receptor B (IL-8RB) antagonist that has previously been shown to inhibit IL-8-based cancer cell invasion, and to possess in vivo anti-inflammatory and anti-nociceptive effects. The present study presented an evidence for the cell cycle-targeting activity of SB in a panel of p53-mutant human cancer cell lines of different origin, and investigated the underlying molecular mechanisms. A combination of cell cycle analysis, immunocytometry, immunoblotting, and RNA interference revealed that SB induced a BubR1-dependent mitotic arrest. Mechanistically, SB was shown to possess a microtubule destabilizing activity evidenced by hyperphosphorylation of Bcl2 and BclxL, suppression of microtubule polymerization and induction of a prometaphase arrest. Molecular docking studies suggested that SB has a good affinity toward vinblastine-binding site on β-tubulin subunit. Of note, SB265610 which is a close structural analog of SB225002 with a potent IL-8RB antagonistic activity did not exhibit a similar antimitotic activity. Importantly, in P-glycoprotein overexpressing NCI/Adr-Res cells the antitumor activity of SB was unaffected by multidrug resistance. Interestingly, the mechanisms of SB-induced cell death were cell-line dependent, where in invasive hepatocellular carcinoma HLE cells the significant contribution of BAK-dependent mitochondrial apoptosis was demonstrated. Conversely, SB activated p38 MAPK signaling in colorectal adenocarcinoma cells SW480, and pharmacologic inhibition of p38 MAPK activity revealed its key role in mediating SB-induced caspase-independent cell death. In summary, the present study introduced SB as a promising antitumor agent which has the potential to exert its activity through dual mechanisms involving microtubules targeting and interference with IL-8-drivin cancer progression.-
dc.publisherElsevier-
dc.titleMolecular mechanisms of the antitumor activity of SB225002: a novel microtubule inhibitor-
dc.title.alternativeMolecular mechanisms of the antitumor activity of SB225002: a novel microtubule inhibitor-
dc.typeArticle-
dc.citation.titleBiochemical Pharmacology-
dc.citation.number12-
dc.citation.endPage1752-
dc.citation.startPage1741-
dc.citation.volume85-
dc.contributor.affiliatedAuthorBo Yeon Kim-
dc.contributor.alternativeNameGoda-
dc.contributor.alternativeNameKoyama-
dc.contributor.alternativeNameSowa-
dc.contributor.alternativeNameElokely-
dc.contributor.alternativeNameYoshida-
dc.contributor.alternativeName김보연-
dc.contributor.alternativeNameSakai-
dc.identifier.bibliographicCitationBiochemical Pharmacology, vol. 85, no. 12, pp. 1741-1752-
dc.identifier.doi10.1016/j.bcp.2013.04.011-
dc.subject.keywordBAK-
dc.subject.keywordMicrotubule destabilizer-
dc.subject.keywordMitochondrial apoptosis-
dc.subject.keywordMitotic arrest-
dc.subject.keywordp38 MAPK-
dc.subject.keywordSB225002-
dc.subject.keywordVinblastine-binding site-
dc.subject.localBAK-
dc.subject.localBak-
dc.subject.localMicrotubule destabilizer-
dc.subject.localMitochondrial apoptosis-
dc.subject.localmitotic arrest-
dc.subject.localMitotic arrest-
dc.subject.localp38 MAP kinase-
dc.subject.localp38 mitogen-activated protein kinase (p38 MARK)-
dc.subject.localP38 MAPK-
dc.subject.localp38 mitogen-activated protein kinase-
dc.subject.localp38 MAPK-
dc.subject.localp38MAPK-
dc.subject.localSB225002-
dc.subject.localVinblastine-binding site-
dc.description.journalClassY-
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Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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