MJ-66 induces cell death and synergizes with minocycline in malignant gliomas

• Main Authors: I-ChenLu, 呂依真
• Other Authors: Po-Wu Gean
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/81708003698561494413

碩士 === 國立成功大學 === 藥理學研究所 === 101 === Malignant gliomas are the most prevalent primary brain tumor in adults and are usually growing rapidly, life-threatening and invasive. Despite recent advances in treatment of malignant gliomas, the prognosis of patients remains very poor. Most patients with malignant gliomas succumb to disease within only 12 to 15 months. In the previous study, our lab found that 2-(Naphthalene-1-yl)-6-pyrrolidinyl- 4-quinazolinone (MJ-66), a synthetic quinazolinone analog, significantly induced glioma cell death by G2/M phase arrest and mitotic catastrophe. However, the detailed mechanisms of MJ-66 against malignant gliomas remain unclear. Several studies have shown that mitotic catastrophe is associated with DNA damage. Besides, combination therapy is believed that could increase therapeutic effects and may contribute to enhance the survival of patients. In previous studies, our lab also found that minocycline (Mino) induced glioma cell death through autophagy as a promising agent against malignant gliomas. Thus, the aim of this study is to investigate whether MJ-66 induces glioma cell death through DNA damage and has synergistic effects with minocycline. We found that MJ-66 induced γH2AX activation after treated with MJ-66 in a time-dependent manner. Subsequently, MJ-66 interfered with G2/M DNA damage checkpoint through increasing phosphorylated levels of Chk1 and Cdc25C. Besides, UCN-01 (Chk1 inhibitor) reversed MJ-66-induced activations of Cdc25C and caspase 3. Intracranial glioma xenograft animal model showed that MJ-66 could inhibit tumor growth and prolong survival time. These results indicated that MJ-66 induced glioma cells DNA damage, Chk1/Cdc25C pathway activation and had antineoplastic effects in the animal model. Further, we used a pharmacological combination to investigate the effects of MJ-66 and Mino in gliomas. We found that the combined treatment of MJ-66 and Mino had synergistic effects on growth inhibition and cytotoxicity. We also found that the combination of MJ-66 and Mino did not increase the activity of caspase 3 and affect autophagy. However, we found that the combined effects of MJ-66 and Mino were through inducing enhanced DNA damage. Hence, we suggest that the combined effects of MJ-66 and Mino on growth inhibition and cytotoxicity were through inducing enhanced DNA damage. Finally, orthotopic glioma animal model indicated that the group of MJ-66 combined with Mino displayed synergistic effects compared to that treated with MJ-66 or Mino only. These findings provide the evidence that the combination of MJ-66 with Mino which may be developed as a new therapeutic strategy against malignant gliomas.