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: Lih-Ching Hsu, David E Durrant, Ching-Chun Huang, Nai-Wen Chi, Riccardo Baruchello, Riccardo Rondanin, Cinzia Rullo, Paolo Marchetti, Giuseppina Grisolia, Daniele Simoni, Ray M Lee
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 4 Pg. 1379-88 (Aug 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 21655917 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Stilbenes
• Tubulin
• Tubulin Modulators
• cis-3,4',5-trimethoxy-3'-aminostilbene
• hemiasterlin
• Kinesins

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Fluorescent Antibody Technique
• Humans
• Kinesins (metabolism)
• Mice
• Microtubules (drug effects, metabolism)
• Oligopeptides (chemistry, pharmacology)
• Polymerization (drug effects)
• Signal Transduction (drug effects)
• Spindle Apparatus (drug effects, metabolism)
• Stilbenes (pharmacology)
• Treatment Outcome
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology)
• Xenograft Model Antitumor Assays