Abstract
Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (HL66) induced cell death with the large cells and multiple micronuclei in M21 skin cancer cells. We demonstrated that HL66-induced cell death is caspase-independent and accompanied by the failure of cell cycle progression. Therefore, HL66-induced cell death may be a mitotic catastrophe. HL66 inhibits the dephosphorylation on Thr14 or Tyr15 of cyclin-dependent kinase (Cdk) 1 and the formation of Cdk1/cyclin B1 complex, which might be associated with cell cycle arrest at the S and G2/M phases. HL66 is an antimicrotubule agent by molecular modeling on the basis of ligand binding to tubulin molecule. Furthermore, we also demonstrated that HL66, like vinblastine, is a tubulin-destabilizing agent via microtubule disruption in M21 cells. These results describe a novel pharmacological property of HL66 as a microtubule inhibitor, which may make it an attractive new agent for the treatment of skin cancer.
Footnotes
This work was supported by the National Science Council of the Republic of China [Grants NSC 97-2320-B-039-005-MY3, CMU99-COL-09].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.176115.
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ABBREVIATIONS:
- Cdk
- cyclin-dependent kinase
- AIF
- apoptosis-inducing factor
- DAPI
- 4′,6-diamidino-2-phenylindole dihydrochloride
- DMSO
- dimethyl sulfoxide
- FITC
- fluorescein isothiocyanate
- HL66
- 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone
- HRP
- horseradish peroxidase
- PBS
- phosphate-buffered saline
- PI
- propidium iodide
- PAGE
- polyacrylamide gel electrophoresis
- TBST
- Tris-buffered saline with Tween 20.
- Received December 7, 2010.
- Accepted June 6, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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