title: Bortezomib-enhanced radiosensitization through the suppression of radiation-induced nuclear factor-κB activity in human oral cancer cells.
abstract: Oral cancer cells have a significantly augmented nuclear factor-κB (NF-κB) activity and the inhibition of this activity suppresses tumor growth. Bortezomib is a proteasome inhibitor and a drug used for molecular-targeted therapy (targets NF-κB). In this study, we investigated whether bortezomib would be effective as an inhibitor of proliferation and a radiosensitizer for the treatment of oral cancer. We demonstrate that bortezomib inhibits NF-κB activity and cell proliferation. The combined treatment with bortezomib and radiation (RT) suppressed NF-κB activity and cell growth in vitro and in vivo compared with RT treatment alone. To investigate the mechanisms by which bortezomib suppresses tumor growth, the expression of signaling molecules downstream of NF-κB were examined by ELISA. The combined treatment significantly inhibited the radiation-induced production of angiogenic factors and decreased the number of blood vessels in the tumor tissues. Although the expression of anti-apoptotic proteins was upregulated by RT, bortezomib downregulated the RT-induced expression of these proteins. Moreover, the expression of cleaved poly(ADP-ribose) polymerase in vitro and in vivo was enhanced by bortezomib, indicating that bortezomib inhibits tumor growth by inducing apoptosis. This study clearly demonstrates that bortezomib significantly inhibits tumor growth and that the combined treatment with bortezomib and RT results in a significant inhibition of tumor growth. The mechanisms underlying the inhibition of tumor growth by bortezomib include the suppression of angiogenesis and the induction of apoptosis. A novel molecular targeting therapy including bortezomib may be effective in the treatment of oral cancer by suppressing NF-κB activity.
authors: Department of Oral Surgery, Subdivision of Molecular Oral Medicine, Division of Integrated Sciences of Translational Research, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima 770-8504, Japan. ttama@dent.tokushima-u.ac.jp
authors: Tetsuya
authors: T
authors: Tamatani
authors: Natsumi
authors: N
authors: Takamaru
authors: Kanae
authors: K
authors: Hara
authors: Makoto
authors: M
authors: Kinouchi
authors: Nobuyuki
authors: N
authors: Kuribayashi
authors: Go
authors: G
authors: Ohe
authors: Daisuke
authors: D
authors: Uchida
authors: Kenji
authors: K
authors: Fujisawa
authors: Hirokazu
authors: H
authors: Nagai
authors: Youji
authors: Y
authors: Miyamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000528:radiation effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051996:Transcription Factor RelA / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D051996:Transcription Factor RelA; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D011065:Poly(ADP-ribose) Polymerases