title: MJ-66 induces malignant glioma cells G2/M phase arrest and mitotic catastrophe through regulation of cyclin B1/Cdk1 complex.
abstract: Malignant gliomas are among the most devastating cancers as they are resistant to many kinds of treatment. Despite recent advances in the diagnosis and treatment, the prognosis of patients remains very poor and the development of new drug is urgently needed. Here, we report that a synthetic quinazolinone analog 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (MJ-66) induced glioma cell death. Immunofluorescence staining showed that MJ-66-induced cell death was associated with multinucleated phenotype and multipolar spindles that were typical characteristics of mitotic catastrophe. Flow cytometry analysis revealed that MJ-66 caused glioma cell cycle arrest at G2/M phase and increased the proportion of polyploidy cells. Western blotting indicated that the expression of cyclin B1, Cdk1 pY15 and Cdk1 increased after treatment with MJ-66. MJ-66 effectively inhibited tumor growth and induced apoptosis in the xenograft animal model of U87 human glioma cells. Together, these results suggest that MJ-66 inhibited malignant gliomas growth through inducing mitotic catastrophe by interference with G2/M cell cycle checkpoint which may open a new avenue for the treatment of malignant gliomas.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Lu
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Tai-Lin
authors.initials: TL
authors.lastname: Chen
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Ta-Shu
authors.initials: TS
authors.lastname: Song
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan. Electronic address: powu@mail.ncku.edu.tw.
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan; China Medical University Hospital, Taichung, Taiwan. Electronic address: mjhou@mail.cmu.edu.tw.
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C562046:2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone; D000970:Antineoplastic Agents; D056744:Cyclin B1; D011759:Pyrrolidines; D052999:Quinazolinones; D016203:CDC2 Protein Kinase
keywords: 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone; G2/M arrest; Malignant glioma; Mitotic catastrophe; Xenograft animal model
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