Glucocorticoid-mediated inhibition of chemotherapy in ovarian carcinomas.
The glucocorticoid dexamethasone is frequently used as a co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact on the cytotoxic treatment of ovarian carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using established cell lines, primary cell lines freshly isolated from patient material and a xenograft on nude mice. We found a general induction of resistance toward cytotoxic therapy by DEX-co-treatment in most of the examined ovarian cancer cells treated in vitro, ex vivo or in vivo. Resistance occurred independently of cell density and was found at peak plasma levels of dexamethasone and below. Mechanistically, the dexamethasone-induced expression of survival genes may be involved in the resistance. These data show that glucocorticoid-induced resistance is common in ovarian carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients.
Zhang
Chengwen
C
Molecular Urooncology, German Cancer Research Center, Heidelberg, Germany.
Marmé
Alexander
A
Wenger
Till
T
Gutwein
Paul
P
Edler
Lutz
L
Rittgen
Werner
W
Debatin
Klaus-Michael
KM
Altevogt
Peter
P
Mattern
Jürgen
J
Herr
Ingrid
I
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D000093542:Gemcitabine; D000099184:Serum-Glucocorticoid Regulated Kinases
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002945:Cisplatin; D003841:Deoxycytidine; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D000093542:Gemcitabine; D000099184:Serum-Glucocorticoid Regulated Kinases; C517019:DUSP1 protein, human; C517020:Dusp1 protein, mouse