Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth

Aim： Noscapine （NOS） is a non-narcotic opium alkaloid with anti-tumor activity. The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide （TMZ）, bis-chloroethylnitrosourea （BCNU）, or cisplatin （ClS）on human glioblastoma cells. Methods： U87MG human glioblastoma cells were examined. Cell proliferation was quantified using MI-I- assay. Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP. Mouse tumor xenograft model bearing U87MG cells was treated with TMZ （2 mg.kgl.d-1, ip） or ClS （2 mg/kg, ip 3 times a week） alone or in combination with NOS （200 mg.kg＇l.d-1, ig） for 3 weeks. Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 fol- lowing treatment in vivo. The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal＇s organs. Results： NOS （10 or 20 mol/L） markedly increased the anti-proliferation effects of TMZ, BCNU, and ClS on U87MG cells in vitro. The calculated combination index （Cl） values of NOS-CIS, NOS-TMZ, and NOS-BCNU （20 pmol/L） were 0.45, 0.51, and 0.57, respectively, demonstrating synergistic inhibition of the drug combinations. In tumor xenograft models, combined treatment with NOS robustly aug- mented the anti-cancer actions of TMZ and ClS, and showed no detectable toxicity. The combined treatments significantly enhanced the apoptosis, the activated caspase-3 and PARP levels in U87MG cells in vitro, and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo. Conclusion： NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells, thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.