Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells.
The proteasome inhibitor bortezomib (PS341) inhibits the function of the 26S proteasome and has been extensively investigated in the clinical setting of hematologic malignancies. Remarkable efficacy has been reported in the treatment of multiple myeloma, but there have been few studies of its use in the treatment of gastrointestinal malignancy, especially gastric cancer. Here, we demonstrate its efficacy, both alone and in combination with other cytotoxic agents, in gastric cancer cell lines. The human gastric cancer cell lines AZ521, MKN45 and NUGC3 were used as experimental models. Bortezomib produced significant growth inhibition in these cells (mean IC50 values: 1.26, 9.44 and 8.63 micromol/l, respectively) and was also observed to decrease the activity of the extracellular signal-regulated kinase 1/2 and Akt signal pathways, increasing the accumulation of p21. Cell-cycle analysis revealed that a low concentration of bortezomib (10-100 nmol/l) increased accumulation in the G1 phase. Moreover, bortezomib showed synergistic growth inhibition in combination with the conventional cytotoxic agents 5-fluorouracil, paclitaxel, doxorubicin and SN-38, and also downregulates the activity of nuclear factor -kappaB, which is induced by these agents. Our results demonstrate that bortezomib could be an effective antitumor agent in the treatment of gastric cancer, both as single-agent therapy and in combination with conventional chemotherapeutic agents.
Fujita
Takeo
T
Department of Cancer and Thoracic Surgery, Okayama University School of Medicine, Okayama, Japan.
Doihara
Hiroyoshi
H
Washio
Kazuhiro
K
Ino
Hideo
H
Murakami
Masakazu
M
Naito
Minoru
M
Shimizu
Nobuyoshi
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease