title: Tat-SmacN7 induces radiosensitization in cancer cells through the activation             of caspases and induction of apoptosis.
abstract: A major concern in cancer therapy is resistance of tumors such as human non-small cell lung cancer and esophageal cancer to radiotherapy. Intrinsic radioresistance of these cancer cells limits therapeutic efﬁciency. Here, we determined in two cancer cell lines the potential radiosensitizing activity of Tat-SmacN7, a small molecule compound, which mimics the activity of Smac, a mitochondrial protein released during apoptosis. We found that Tat-SmacN7 can enter the cells and promote RNA expression and the activity of caspase-3, -8 and -9 and sensitized the cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.5-1.6. Tat-SmacN7 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases. Consistently, blockage of caspase activation, through treatment with a caspase inhibitor, z-VAD-fmk, inhibited apoptosis and abrogated Tat-SmacN7 radiosensitization. Our study demonstrates that Tat-SmacN7 also has radiosensitization effects in vivo, so it could be further developed as a novel class of radiosensitizers for the treatment of radioresistant human non-small cell lung cancer and esophageal cancer.
authors: Department of Radiation Hazard Evaluation, Institute of Radiation                     Medicine of Chinese Academy of Medical Science and Peking Union Medical                     College, Tianjin 300192, P.R. China.
authors: Fenghua
authors: F
authors: Chen
authors: Chang
authors: C
authors: Xu
authors: Liqing
authors: L
authors: Du
authors: Yan
authors: Y
authors: Wang
authors: Jia
authors: J
authors: Cao
authors: Yue
authors: Y
authors: Fu
authors: Yanting
authors: Y
authors: Guo
authors: Qiang
authors: Q
authors: Liu
authors: Feiyue
authors: F
authors: Fan
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D015696:Gene Products, tat / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D009368:Neoplasm Transplantation; D010455:Peptides / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D011838:Radiation-Sensitizing Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9