Original article: general thoracicEnhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis
Section snippets
Cells and reagents
The NSCLC cell line H358 was purchased from American Tissue Culture Collection (Manassas, VA). Cells were maintained in RPMI media supplemented with glutamine (1 mmol/L), streptomycin (100 μg/mL)/penicillin (100 U/mL), and 10% of fetal calf serum. Normal human bronchial epithelial cells were purchased from Clonetics Corp (Walkersville, MD) and maintained in bronchial epithelial cell basal media (Clonetics Corp). The 17-AAG, obtained from the Drug Synthesis & Chemistry Branch, Developmental
Depletion of erbB1 and erbB2 expression on H358 cells by 17-AAG
The H358 cells expressed high levels of erbB2 (approximately threefold higher than the level detected on normal human bronchial epithelial cells), with mean fluorescence intensity of 160 ± 11. Exposure of H358 cells to 20 or 80 nmol/L of 17-AAG for 24 hours resulted in a dose-dependent reduction of erbB2 mean fluorescence intensity to 80 ± 6 and 40 ± 8 (p < 0.01 versus baseline controls, n = 3) (Fig 1). Moreover, at the higher dose of 17-AAG, erbB2 expression was completely depleted in 65% of
Comment
Previous studies have demonstrated that members of the erbB superfamily (particularly erbB1 and erbB2, which are frequently overexpressed in NSCLC cells) play important roles in mediating the response of tumor cells to cytotoxic stress and modulating their susceptibility to chemotherapeutic agents. Overexpression of erbB2 in cancer cells enhances resistance to various cytotoxic agents including cisplatin and paclitaxel as well as irradiation. Upregulation of DNA repair mechanisms mediated by
Acknowledgements
We acknowledge the superb technical assistance of Shawn Farid, BS, and Arnold Mixon, BS, of the Flow Cytometry Core Facility, Surgery Branch, National Cancer Institute, National Institutes of Health.
References (25)
- et al.
Sequence-dependent enhancement of paclitaxel toxicity in non-small cell lung cancer by 17-allylamino 17-demethoxygeldanamycin
J Thorac Cardiovasc Surg
(1999) - et al.
Prognostic significance of HER-2/neu overexpression in stage I adenocarcinoma of lung
Ann Thorac Surg
(1998) - et al.
Modulation of metastasis phenotypes of non-small cell lung cancer cells by 17-allylamino 17-demethoxy geldanamycin
Ann Thorac Surg
(2000) - et al.
Quantitative analysis of dose-effect relationshipsthe combined effects of multiple drugs or enzyme inhibitors
Adv Enzyme Regul
(1984) - et al.
Antisense blockade of p21/WAF1 decreases radiation-induced G2 arrest in esophageal squamous cell carcinoma
J Surg Res
(1999) - et al.
Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells
J Natl Cancer Inst
(1995) - et al.
Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms
Oncogene
(1996) - et al.
Dual effects of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells
Oncogene
(1998) - et al.
Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent
Cancer Chemother Pharmacol
(1995) - et al.
Depletion of p185/erbB-2, Raf-1, mutant p53 proteins by gendanamycin derivatives correlates with antiproliferative activity
Cancer Chemother Pharmacol
(1997)
The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin
Cancer Chemother Pharmacol
Human breast cancercorrelation of relapse and survival with amplification of the HER-2/neu oncogene
Science
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