Glucocorticoids enhance cytotoxicity of cisplatin via suppression of NF-{kappa}B activation in the glucocorticoid receptor-rich human cervical carcinoma cell line SiHa.
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.
Lu
Yen-Shen
YS
Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Rd, Taipei 10016, Taiwan.
Yeh
Pei-Yen
PY
Chuang
Shuang-En
SE
Gao
Ming
M
Kuo
Min-Liang
ML
Cheng
Ann-Lii
AL
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
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