Dexamethasone as a chemosensitizer for breast cancer chemotherapy: potentiation of the antitumor activity of adriamycin, modulation of cytokine expression, and pharmacokinetics.
Dexamethasone (DEX) is mainly used as an anti-emetic agent in cancer therapy. We have recently demonstrated that DEX pretreatment increases the antitumor activity of the cancer chemotherapeutic agents carboplatin and gemcitabine, and decreases host toxicity in nude mouse xenograft models of human cancer. However, the underlying mechanisms are not fully understood. The present study was designed to determine the effects of DEX pretreatment on the anticancer activity of adriamycin (ADR) in a syngeneic model of breast cancer (4T1), emphasizing the effects of DEX on cytokine expression and modulation of ADR pharmacokinetics. We have demonstrated five major new findings about DEX pretreatment: a) it enhances the therapeutic effect of ADR, inducing almost complete inhibition of tumor growth; b) it increases tumor ADR accumulation; c) it modulates the expression of cytokines produced by the tumor, increasing TNFalpha and decreasing IL-1beta and VEGF expression; d) it enhances the effects of ADR on induction of apoptosis and inhibition of cell proliferation; and e) it suppresses nuclear NFkappaB activation and inhibits ADR-induced NFkappaB activation, possibly via IkappaB up-regulation. These findings suggest that DEX can be used as a chemosensitizer and chemoprotectant. These results provide a rationale for the expanded clinical use of DEX for cancer therapy.
Wang
Hui
H
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA. hui.wang@ccc.uab.edu
Wang
Ying
Y
Rayburn
Elizabeth R
ER
Hill
Donald L
DL
Rinehart
John J
JJ
Zhang
Ruiwen
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone; D004317:Doxorubicin