Differential modulatory effects of acetazolomide and dexamethasone on temozolomide-induced apoptosis in human malignant glioblastoma U87MG cells
Authors: Makiko Nagamine, Yasuyuki Sadzuka, Takashi Sonobe
Journal: Cancer Research (2006)

2128  In recent years, cancer chemotherapy has improved with the development of new drugs and new treatments. However, there are many problems including antitumor drugs induced adverse reaction. Recently, many studies on drug delivery systems for enhancement of antitumor activity and the reduction of adverse reaction have been reported with commercial antitumor drugs. Furthermore, the enhancement of antitumor activity was observed by biochemical modulation applied in clinical therapy. However, the increased activity of antitumor drug by biochemical modulation accompany with the increase of adverse reaction on the present condition. Thus, improvement of the therapeutic index may not be achieved. Therefore, the development of more effective modulator without elevation of the adverse reaction has been expected. Curcumin is a phenolic compound from the plant Curcuma longa (Linn). It is widely used as a coloring and flavoring component in food. It is clarified that curcumin has wide range of pharmacological activities including anti-inflammatory or antioxidative activity. On the other hand, Doxorubicin (DOX) is one of the most effective anthracycline antibiotics with broad antitumor spectrum and is used widely in clinical human cancer therapy. However DOX induced severe cardiotoxicity as an adverse reaction is dose limiting factor. The cardiotoxicity of DOX is related with the increment of lipid peroxide (LPO) level in the heart. It is considered that this increase in the LPO level is caused by the decrease of GSHpx activity. In this study, we examined the effects of curcumin on antitumor activity and adverse reaction induced by DOX. GOT and GPT activities in serum of mice, as index of cardiotoxicity and hepatotoxicity, was increased by DOX treatment. However, the combination of curcumin with DOX was tendency to decrease these activities. Curcumin decreased DOX induced increase of LPO level in heart of mice. In addition, curcumin prevented decrease of GSHpx level by DOX treatment. Namely, we suggested that curcumin may prevent DOX induced adverse reaction with its action including antioxidative effect. On the other hand, the antioxidative effect of curcumin is feared to decrease antitumor activity of DOX. But the combination of curcumin with DOX decreased tumor weight. Thus, we suggested that curucmin enhanced antitumor activity of DOX with decrease of DOX induced adverse reaction. On DOX influx and efflux in tumor cells, curcumin didn’t have significant effects. On the other hand, the combined curcumin at un-cytotoxic concentration enhanced by 2.0 fold cytotoxicity of DOX to tumor cells in culture. These results indicated that the enhancement of antitumor activity of DOX by curcumin is related with effects of curcumin on mechanism of DOX antitumor activity, not increase DOX concentration in tumor cells.In conclusion, it is expected that curcumin is useful modulator with enhancement of antitumor activity and suppression of adverse reaction by DOX.