title: Anti-tumor activity of the proteasome inhibitor bortezomib in gastric cancer.
abstract: The prognosis of unresectable advanced gastric cancer has improved over the last decade due to advances in chemotherapy. However, molecular targeting in gastric cancer therapy has been poorly established and the 5‑year survival rate is still <10%. The proteasome plays a pivotal role in the regulation of cell proliferation, apoptosis and differentiation in a variety of tumor cells. Bortezomib, a selective inhibitor of the proteasome, has prominent effects against several tumor types, including multiple myeloma. We examined the anti-tumor effects of bortezomib on gastric cancer cells in vitro and in subcutaneously transplanted nude mice. We demonstrated that among seven types of gastric cancer cells examined, treatment with bortezomib induced both apoptotic and anti-proliferative effects, resulting in a reduction in cell survival rates. The induction of apoptosis was observed to be dependent on the inhibition of nuclear factor κB (NF-κB) activation and the subsequent production of reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) activation. Interestingly, we observed that those cells with high levels of NF-κB activity were resistant to bortezomib treatment. Additionally, we demonstrated that the activation of the extracellular signal-regulated kinase (ERK1/2) was inhibited following bortezomib treatment, which may contribute to its anti-proliferative effects. We also observed anti‑tumor effects of bortezomib in vivo. Bortezomib is a potential novel molecular targeting drug for the treatment of unresectable advanced gastric cancer.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Wachiko
authors.initials: W
authors.lastname: Nakata
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D048670:MAP Kinase Kinase 4