作者: Song, Ta-Shu ; Hour, Mann-Jen ; Kuo, Sheng-Chu ; Chen, Ching ; Lu, Yi-Liang ; Liu, Wei-Ting ; Lu, I-Chen ; Lee, Kuo-Hsiung ; Chen, Tai-Lin ; Gean, Po-Wu

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.

2014-01-01·American journal of cancer research3区 · 医学

Aggravated DNA damage as a basis for enhanced glioma cell killing by MJ-66 in combination with minocycline.

3区 · 医学

Article

作者: Gean, Po-Wu ; Lu, I-Chen ; Kuo, Sheng-Chu ; Liu, Wei-Ting ; Hour, Mann-Jen

Despite recent advances in the treatment of malignant glomas, the prognosis of patients remains very poor and more efficient therapeutic approaches are urgently needed. In the present study, we investigated whether 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (MJ-66), a synthetic quinazolinone analog, induces glioma cell death through DNA damage. Treatment of C6 glioma cells with MJ-66 resulted in a time-dependent increase in γ-H2AX and increased the appearance of nuclear γ-H2AX foci. MJ-66 interfered with G2/M DNA damage checkpoint through increasing phosphorylated levels of Chk1 and Cdc25C. UCN-01, a Chk1 inhibitor, reversed MJ-66-induced activation of Cdc25C and caspase 3. MJ-66 inhibited tumor growth and prolonged survival time in intracranial glioma xenograft model. The combination of MJ-66 and Mino enhanced DNA damage and synergistically inhibited tumor growth and prolonged survival time in intracranial glioma xenograft model. These results suggest that the combination of MJ-66 and Mino may be developed as a new therapeutic strategy against malignant gliomas.

2011-09-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone Inhibits Skin Cancer M21 Cell Proliferation through Aberrant Expression of Microtubules and the Cell Cycle

3区 · 医学

Article

作者: Wing Cheung Leung ; Wen-Zhi Liu ; Hong-Zin Lee ; Yang-Chang Wu ; Yu-Hao Chang ; Chi-Yu Wu ; Mann-Jen Hour

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.

100 项与 MJ-66 相关的药物交易

登录后查看更多信息