title: Molecular mechanisms of the antitumor activity of SB225002: a novel microtubule inhibitor.
abstract: SB225002 (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.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. agoda@kribb.re.kr
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Goda
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Khaled M
authors.initials: KM
authors.lastname: Elokely
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D053700:Receptors, Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D053700:Receptors, Interleukin-8; C112019:SB 225002; D050257:Tubulin Modulators