title: c-Myc down-regulation is involved in proteasome inhibitor-mediated enhancement             of radiotherapeutic efficacy in non-small cell lung cancer.
abstract: In this study, the effect of MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal-H)             at a low dose on radiotherapeutic efficacy and its accurate mechanism of radiosensitization             were investigated in human non-small cell lung cancer. The effect of MG132 on             ionizing radiation (IR)-induced cytotoxicity, cell proliferation and survival             of A549 cells was evaluated. The protein expression modulated by MG132 and IR             were inspected by Western blot analysis. To determine in vivo radiotherapeutic             efficacy, tumor growth delay was analyzed in a A549 tumor-bearing xenograft mouse             model after single or repeated treatment of MG132 and/or IR. Induction of apoptosis             and change of c-Myc expression in the tumor tissue was explored by histological             analysis. MG132 at a non-toxic dose enhanced the radiation-induced cytotoxicity             of A549 cells, accompanying a significant decrease of c-Myc expression. Suppression             of c-Myc expression by small interfering RNA (siRNA) displayed enhancement of             radiosensitivity similarly to MG132 treatment. Tumor growth in the xenograft mice             was markedly delayed by systemic administration of MG132 combined with IR. In             vivo down-regulation of c-Myc and increased induction of apoptosis were simultaneously             observed in the tumor tissues followed by combinational treatment of MG132 and             IR. The results reveal a novel mechanism for proteasome inhibitor-mediated radiosensitization             in which c-Myc down-regulation is involved.
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Jung
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Chung
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D007976:Leupeptins; C489427:MYC protein, human; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011838:Radiation-Sensitizing Agents; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde