title: Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.
authors.affiliation: Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Ugir Hossain
authors.initials: UH
authors.lastname: Sk
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xingcong
authors.initials: X
authors.lastname: Ren
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Huber-Keener
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D001932:Brain Neoplasms / Q000188:drug therapy*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012643:Selenium / Q000737:chemistry*; D012878:Skin Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D003606:Dacarbazine; D002154:Calpain; D012643:Selenium; D000077204:Temozolomide