title: 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone inhibits skin cancer M21 cell proliferation through aberrant expression of microtubules and the cell cycle.
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.
authors.affiliation: Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Yang C
authors.initials: YC
authors.lastname: Wu
authors.forename: Mann J
authors.initials: MJ
authors.lastname: Hour
authors.forename: Wing C
authors.initials: WC
authors.lastname: Leung
authors.forename: Chi Y
authors.initials: CY
authors.lastname: Wu
authors.forename: Wen Z
authors.initials: WZ
authors.lastname: Liu
authors.forename: Yu H
authors.initials: YH
authors.lastname: Chang
authors.forename: Hong Z
authors.initials: HZ
authors.lastname: Lee
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents; D056744:Cyclin B1 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D015195:Drug Design; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014343:Trypan Blue; D014404:Tubulin; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: C562046:2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone; D017304:Annexin A5; D000970:Antineoplastic Agents; D004396:Coloring Agents; D056744:Cyclin B1; D004273:DNA, Neoplasm; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D052999:Quinazolinones; D014404:Tubulin; D050257:Tubulin Modulators; D016203:CDC2 Protein Kinase; D020169:Caspases; D014343:Trypan Blue