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2 results on '"Sumikawa T"'

1. Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.

Author

Sumikawa T, Shigeoka Y, Igishi T, Suyama H, Yamasaki A, Hashimoto K, Matsumoto S, Takeda K, Ueda Y, and Shimizu E

Subjects
Antibodies, Monoclonal, Humanized, Antineoplastic Agents antagonists & inhibitors, Antineoplastic Agents pharmacology, Breast Neoplasms enzymology, Cell Cycle drug effects, Dexamethasone adverse effects, Down-Regulation drug effects, Drug Combinations, Drug Evaluation, Preclinical, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Oncogene Protein v-akt physiology, Paclitaxel pharmacology, Phosphorylation drug effects, Trastuzumab, Tumor Cells, Cultured, Antibodies, Monoclonal pharmacology, Breast Neoplasms pathology, Cell Proliferation drug effects, Dexamethasone pharmacology, Oncogene Protein v-akt metabolism
Abstract

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.

Published
2008

2. Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells.

Author

Morita M, Suyama H, Igishi T, Shigeoka Y, Kodani M, Hashimoto K, Takeda K, Sumikawa T, and Shimizu E

Subjects
Carcinoma, Non-Small-Cell Lung, Cell Division drug effects, Cell Line, Tumor, Chromones pharmacology, DNA, Neoplasm drug effects, Enzyme Inhibitors pharmacology, Humans, Kinetics, Lung Neoplasms, Morpholines pharmacology, Paclitaxel toxicity, Retinoblastoma Protein drug effects, Cell Cycle drug effects, Cell Survival drug effects, Dexamethasone pharmacology, Paclitaxel antagonists & inhibitors, Retinoblastoma Protein metabolism
Abstract

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.

Published
2007

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