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 skin cancer M21 cells. We demonstrated that HL66-induced cell death is caspase-independent and accompanied by the failure of the cell cycle progression. Therefore, HL66-induced cell death may be a mitotic catastrophe. HL66 inhibits the dephosphorylation on Thr14 or Tyr15 of Cdk1 and the formation of Cdk1/cyclin B1 complex, which might be associated with cell cycle arrest at S and G2/M phase. 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 treatment of skin cancer.
- 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone
- Cdk1/cyclin B1 complex
- anti-microtubule agent
- cell cycle arrest
- mitotic catastrophe
- skin cancer M21 cells
- Received December 7, 2010.
- Revision received June 3, 2011.
- Accepted June 6, 2011.
- The American Society for Pharmacology and Experimental Therapeutics