Anti-neoplastic effects of two transcription inhibitors, M(4)N and maltose-M(3)N against mouse and human tumors.

摘要

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was previously demonstrated to be a potent tumor growth inhibitor by blocking the cell cycle specific, Sp1-regulated transcription of CDC2 (Cdk1) gene in several mouse and human cancer cells. The present studies were undertaken to further examine the antineoplastic natures of M4N (88, 104) and its water soluble analogue, maltose-tri-O-methyl NDGA (Maltose-M3N). M4N treatment suppressed the Sp1-regulated survivin expression, a member of the inhibitor of apoptosis family and activated the mitochondrial apoptotic pathway. Cell division of M4N treated C3 cells was transiently after transfection of an exogenous CDC2 gene copy under the control of the Sp1-independent cytomegalovirus (CMV) promoter; caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. M4N treatment suppressed the in vitro growth of MCF7, Hep3B, HT29, LNCaP, and K562 human cancer cells with IC 50 values of 5 muM to 15 muM. Systemic treatment of M4N also effectively inhibited the in vivo growth of xenograft tumors of the human cancer cell lines, accompanied by reductions in both CDC2 and survivin gene expression.; Similarly, Maltose-M3N treatment inhibited the growth of the five human cancer cells with IC50 values of 20 muM to 40 muM, with reduced CDC2 and survivin expression, leading to apoptosis. Daily intratumoral injection of 10∼40 mg of Maltose-M3N into C3 tumors for 4 days also induced apoptosis throughout the tumors with marked reductions in CDC2 and survivin protein.; Furthermore, multidrug resistance (MDR) continues to be a major obstacle for anticancer therapy. One of the principle factors implicated in MDR is the overexpression of P-glycoprotein (Pgp), the product of the MDR1 gene. We used M4N to inhibit Sp1-regulated MDR1 gene expression and restore doxorubicin sensitivity to the multidrug resistant NCI/ADR-RES human breast cancer cells. M4N inhibited MDR1 gene expression in the resistant cells and reversed the MDR phenotype as measured by rhodamine-123 retention.; As each of the proteins CDC2, survivin, and Pgp are profoundly involved in cell proliferation, apoptosis, and multiple drug resistance in cancer, the findings of this thesis report suggest that M4N and Maltose-M 3N may effectively control cancer that have these genetic lesions.