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

摘要

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.