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 TNFα and decreasing IL-1β and VEGF expression; d) it enhances the effects of ADR on induction of apoptosis and inhibition of cell proliferation; and e) it suppresses nuclear NFκB activation and inhibits ADR-induced NFκB activation, possibly via IκB 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.

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