Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor
Journal
Investigational New Drugs
Journal Volume
30
Journal Issue
4
Pages
1379-1388
Date Issued
2012
Author(s)
Durrant D.E.
Huang C.-C.
Chi N.-W.
Baruchello R.
Rondanin R.
Rullo C.
Marchetti P.
Grisolia G.
Simoni D.
Lee R.M.
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. ? Springer Science+Business Media, LLC 2011.
Subjects
Anticancer; Hemiasterlins; Stilbene 5c; Tubulin; Vincristine
Other Subjects
3,4',5 trimethoxy 3' aminostilbene; bf 65; bf 78; cyclin dependent kinase 1; hemiasterlin derivative; kinesin 5; monastrol; nocodazole; paclitaxel; protein bcl 2; stilbene derivative; tubulin modulator; unclassified drug; vincristine; animal experiment; animal model; apoptosis; article; cancer cell; cell cycle arrest; cell cycle G2 phase; cell cycle M phase; centrosome; concentration response; controlled study; drug cytotoxicity; drug efficacy; drug potentiation; drug structure; immunofluorescence test; in vitro study; in vivo study; maximum tolerated dose; microtubule assembly; mitosis inhibition; mitosis spindle; mouse; neoplasm; nonhuman; priority journal; protein phosphorylation; signal transduction; tumor xenograft; Animals; Antineoplastic Agents; Cell Cycle; Cell Death; Cell Line, Tumor; Drug Synergism; Fluorescent Antibody Technique; Humans; Kinesin; Mice; Microtubules; Mitotic Spindle Apparatus; Oligopeptides; Polymerization; Signal Transduction; Stilbenes; Treatment Outcome; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays
Type
journal article