Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death

• Published in: PloS one 2012-04, Vol.7 (4), p.e35104
• Main Authors: Cheng, Yan, Sk, Ugir Hossain, Zhang, Yi, Ren, Xingcong, Zhang, Li, Huber-Keener, Kathryn J, Sun, Yuan-Wan, Liao, Jason, Amin, Shantu, Sharma, Arun K, Yang, Jin-Ming
• Format: Article
• Language: English
• Subjects: Alkylation; Analysis; Animals; Anticancer properties; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - therapeutic use; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - genetics; Autophagy; Autophagy - drug effects; Beclin-1; Biochemistry; Biology; Brain cancer; Brain Neoplasms - drug therapy; Calpain; Calpain - antagonists & inhibitors; Calpain - physiology; Cell death; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Dacarbazine - analogs & derivatives; Dacarbazine - chemistry; Dacarbazine - therapeutic use; Deoxyribonucleic acid; DNA; DNA repair; Encephalitis; Glioma; Glioma - drug therapy; Glioma cells; Gliomas; Hershey, Milton Snavely; Humans; Male; Medicine; Melanoma; Melanoma - drug therapy; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred BALB C; Mice, Nude; Mortality; mRNA; Phagocytosis; Pharmacology; Physicians; Proteins; RNA; Selenium; Selenium (Chemical element); Selenium - chemistry; Skin cancer; Skin Neoplasms - drug therapy; Temozolomide; Toxicity; Tumor cells; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035104

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. Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.