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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Animals, Antineoplastic Agents, Alkylating, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Brain Neoplasms, Calpain, Cell Line, Tumor, Dacarbazine, Glioma, Humans, Male, Melanoma, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Nude, Selenium, Skin Neoplasms, Temozolomide, Xenograft Model Antitumor Assays.
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Does rational incorporation of selenium into temozolomide elicit superior antitumor activity associated with both apoptotic and autophagic cell death? Context: The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se.
assistant
Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug. Final Decision: yes