title: Glucocorticoids enhance cytotoxicity of cisplatin via suppression of NF-{kappa}B activation in the glucocorticoid receptor-rich human cervical carcinoma cell line SiHa.
abstract: Glucocorticoids (GCs) are commonly co-administered with cisplatin in the treatment of patients with carcinomas to prevent drug-induced allergic reaction, nausea and vomiting. Although GC receptor (GR) is ubiquitous in carcinoma cells and has been linked to signal transduction pathways pertinent to cell growth and apoptosis, little is known regarding the possible effect of GC on the chemosensitivity of carcinomas. Our previous study demonstrated that dexamethasone (DEX) enhances the cytotoxicity to cisplatin in a GR-rich human cervical carcinoma cell line, SiHa. In this study, we found that this cisplatin cytotoxicity-enhancing effect of DEX correlated well with its effect on abrogating the cisplatin-induced activation of nuclear factor kappa B (NF-kappaB). RU486, a structural homologue of DEX, partially reversed this cytotoxicity-enhancing effect of DEX, a finding consistent with the well-known partial reversing effect of RU486 on DEX-induced NF-kappaB suppression. Furthermore, expression of a dominant-negative truncated IkappaBalpha gene in SiHa cells completely abolished the cisplatin cytotoxicity-enhancing effect of DEX. Our data suggest that the specific action of DEX on GR may enhance the cytotoxicity of cisplatin in selected GR-rich cancer cells by suppressing NF-kappaB activation.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Rd, Taipei 10016, Taiwan.
authors.forename: Yen-Shen
authors.initials: YS
authors.lastname: Lu
authors.forename: Pei-Yen
authors.initials: PY
authors.lastname: Yeh
authors.forename: Shuang-En
authors.initials: SE
authors.lastname: Chuang
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D005786:Gene Expression Regulation / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis; D015735:Mifepristone / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000032:analysis; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006727:Hormone Antagonists; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D051028:bcl-2-Associated X Protein; D015735:Mifepristone; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D002945:Cisplatin