Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.
The combination of trastuzumab with paclitaxel (PTX) is an important option for the treatment of HER2-positive breast cancer. Dexamethasone (Dex) premedication is routinely used in the treatment with PTX. The interactions among Dex, PTX and trastuzumab were evaluated in BT-474 cells. Dex interfered with trastuzumab-induced cell growth inhibition without clear effects on PTX-induced cytotoxicity. Trastuzumab dephosphorylated retinoblastoma protein (pRB). Dex restored this trastuzumab-induced dephosphorylation of pRB and released trastuzumab-induced G1 arrest. Trastuzumab suppressed AKT activity without affecting ERK activity. A specific inhibitor for the phosphatidylinositol 3-kinase/AKT pathway, LY294002, inhibited cell growth and AKT and pRB phosphorylation. Dex restored the trastuzumab-induced suppression of AKT without affecting ERK activity. It was concluded that Dex interferes with trastuzumab-induced cell growth inhibition, at least partially, through the restoration of trastuzumab-induced AKT suppression and subsequent pRB dephosphorylation in BT-474 breast cancer cells. These observations support the development of new chemotherapeutic regimens without glucocorticoid premedication.
Sumikawa
Takashi
T
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Shigeoka
Yasushi
Y
Igishi
Tadashi
T
Suyama
Hisashi
H
Yamasaki
Akira
A
Hashimoto
Kiyoshi
K
Matsumoto
Shingo
S
Takeda
Kenichi
K
Ueda
Yasuto
Y
Shimizu
Eiji
E
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism* / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004338:Drug Combinations; D003907:Dexamethasone; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000068878:Trastuzumab; D017239:Paclitaxel