Combination effect between bortezomib and tumor necrosis factor alpha on gefitinib-resistant non-small cell lung cancer cell lines.
Tumor cells that have acquired resistance to gefitinib may complicate the future treatment of patients with non-small cell lung cancer (NSCLC). To investigate the mechanisms of acquired resistance, an acquired gefitinib-resistant cell line, PC-9/ZD2001, has been established using a gefitinib-sensitive NSCLC cell line, PC-9. PC-9/ZD2001 showed collateral sensitivity to tumor necrosis factor (TNF)-alpha. Bortezomib is a proteasome inhibitor and enhances TNF-alpha-induced cell death. These observations suggest that the combination of bortezomib and TNF-alpha might have effects against gefitinib-resistant cells. To verify this hypothesis, a combination effect between these drugs was examined using MTT assay and immunoblotting. This combination showed synergistic cytotoxic effect in NSCLC cell lines with either acquired or intrinsic gefitinib resistance. However, this combination effect was not observed in gefitinib-sensitive cells. On the other hand, bortezomib inhibited TNF-alpha-induced IkappaB degradation in all cell lines. From these observations, it is concluded that the combination of bortezomib and TNF-alpha could be used to overcome gefitinib-resistance.
Kusumoto
Sojiro
S
Division of Allergology and Respiratory Medicine, Department of Internal Medicine, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan.
Sugiyama
Tomohide
T
Ando
Koichi
K
Hosaka
Takamichi
T
Ishida
Hiroo
H
Shirai
Takao
T
Yamaoka
Toshimitsu
T
Okuda
Kentaro
K
Hirose
Takashi
T
Ohnishi
Tsukasa
T
Inoue
Fumiko
F
Kanome
Tomoko
T
Kadofuku
Tsuyoki
T
Saijo
Nagahiro
N
Adachii
Mitsuru
M
Ohmori
Tohru
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D066246:ErbB Receptors; D000077156:Gefitinib