Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells.
Paclitaxel is used frequently for the treatment of patients with non-small cell lung cancer. Hypersensitivity reactions remain one of the major adverse events in the clinical use of paclitaxel. Glucocorticoids are used to prevent these adverse events. This study was carried out in order to clarify the effect of glucocorticoids on paclitaxel-induced cytotoxity of cancer cells. Pretreatment with 10 microM of dexamethasone inhibited ERK activation and subsequent retinoblastoma protein (pRB) phosphorylation, and reduced sensitivity to paclitaxel in A549 cells. Then, we utilized ERK (PD98059) and AKT (LY294002) inhibitors. PD98059 and LY294002 effectively suppressed pRB phosphorylation in A549 cells. Dexamethasone (10 microM) suppressed ERK activity as well as PD98059, although it did not affect AKT activity. Furthermore, the combinations of paclitaxel with PD98059 or LY294002 were similarly antagonistic. Our observation in this study raised the possibility that dexamethasone pretreatment antagonizes paclitaxel-induced cytotoxicity through ERK suppression and pRB dephosphorylation. These observations support the development of new generation taxane-based chemotherapy without glucocorticoid premedication.
Morita
Masato
M
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Suyama
Hisashi
H
Igishi
Tadashi
T
Shigeoka
Yasushi
Y
Kodani
Masahiro
M
Hashimoto
Kiyoshi
K
Takeda
Kenichi
K
Sumikawa
Takashi
T
Shimizu
Eiji
E
D002289:Carcinoma, Non-Small-Cell Lung; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D009025:Morpholines / Q000494:pharmacology; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*
D002867:Chromones; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009025:Morpholines; D016160:Retinoblastoma Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003907:Dexamethasone; D017239:Paclitaxel