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  • Title: 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone inhibits skin cancer M21 cell proliferation through aberrant expression of microtubules and the cell cycle.
    Author: Wu YC, Hour MJ, Leung WC, Wu CY, Liu WZ, Chang YH, Lee HZ.
    Journal: J Pharmacol Exp Ther; 2011 Sep; 338(3):942-51. PubMed ID: 21652781.
    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 G(2)/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.
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