Dexamethasone-induced cytotoxic activity and drug resistance effects in androgen-independent prostate tumor PC-3 cells are mediated by lipocortin 1.
We have examined the effects that dexamethasone (DEX), alone or in combination with doxorubicin (DOX), cisplatin (CDDP), or etoposide (VP-16), exerts on the growth of the androgen-independent prostate cancer PC-3 cells. DEX exhibited only a limited cytotoxicity (growth inhibition of about 28% or 20% after 24 or 72 h of exposure, respectively, in the range of DEX 10-100 nM) and did not induce apoptosis in the cells. This cytotoxicity of DEX was mimicked by an active peptide (peptide Ac2-26) drawn from the human lipocortin 1 N-terminus region and abrogated by an antibody to human lipocortin 1. Two inhibitors of arachidonic acid metabolism, tenidap and indomethacin, also caused cytotoxicity. The cytotoxic effects of DEX in combination with DOX, CDDP, or VP-16 were antagonistic when the steroid was administered 3 h before or simultaneously with the drugs. Other schedule-dependency experiments further clarified that, at least in the case of the combination with DOX, it is the steroid that desensitizes the cells to the drug. When peptide Ac2-26, tenidap, or indomethacin were tested in combination with DOX, antagonism was also observed. DEX treatment neither modified the ability of the cells to accumulate DOX nor changed their weak expression of P-glycoprotein. PC-3 cells also produce IL-6, which autocrinally stimulates their growth, and whose gene expression may be reduced by glucocorticoids. In the present experiments DEX only slightly decreased the production and secretion of IL-6 by the cells. The present findings suggest that the slight cytotoxic activity and the drug resistance effects of DEX on PC-3 cells are mediated by induction of lipocortin 1 and inhibition of arachidonic acid metabolism, with no relationship to downregulation of IL-6 levels. These findings indicate also that the combination of DEX with conventional chemotherapeutic agents may result in antagonistic antitumor effects.
Carollo
M
M
Institute of Pharmacology, Faculty of Medicine, University of Palermo, Italy.
Parente
L
L
D'Alessandro
N
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000728:Androgens / Q000494:pharmacology; D017305:Annexin A1 / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000728:Androgens; D017305:Annexin A1; D015850:Interleukin-6; D016718:Arachidonic Acid; D003907:Dexamethasone; D004317:Doxorubicin