title: Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor.
abstract: Hemiasterlins are cytotoxic tripeptides with antimicrotubule activity originally isolated from marine sponges. We have developed new hemiasterlin derivatives BF65 and BF78 that are highly potent to induce cancer cell death in the low nanomolar range. Examination of their mechanisms of cell cycle arrest and disruption of microtubules revealed an unusual characteristic in addition to anti-tubulin effect. Immunofluorescence staining revealed that A549 lung carcinoma cells treated with BF65 or BF78 exhibited both monopolar and multipolar mitotic spindles. Centrosomes were separated with short spindle microtubules in cells with multipolar spindles. In vitro tubulin polymerization assay confirmed that both BF65 and BF78 were highly potent to inhibit tubulin polymerization. These two compounds induced the formation of monoastral spindles suggesting that they might be inhibitors of mitotic kinesins such as KSP/Eg5. However, kinetic measurement of microtubule activated kinesin ATPase activity demonstrated that unlike the positive control monastrol, neither BF65 nor BF78 suppressed KSP/Eg5 activity. Hence the effect may be a variant form of tubulin inhibition. Similar to vinca alkaloids, BF compounds synergized with a colchicine site microtubule inhibitor stilbene 5c both in vitro and in vivo, which may provide a potential drug combination in the future clinical application.
authors.affiliation: School of Pharmacy, National Taiwan University, 12F, No 1, Section 1, Jen-Ai Road, Taipei 10051, Taiwan. lhsu@ntu.edu.tw
authors.forename: Lih-Ching
authors.initials: LC
authors.lastname: Hsu
authors.forename: David E
authors.initials: DE
authors.lastname: Durrant
authors.forename: Ching-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rondanin
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rullo
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Grisolia
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Ray M
authors.initials: RM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C529077:cis-3,4',5-trimethoxy-3'-aminostilbene; C467070:hemiasterlin; D016547:Kinesins