Enhancement by other compounds of the anti-cancer activity of vitamin D₃ and its analogs

Differentiation therapy holds promise as an alternative to cytotoxic drug therapy of cancer. Among compounds under scrutiny for this purpose is the physiologically active form of vitamin D₃, 1,25-dihydroxyvitamin D₃, and its chemically modified derivatives. However, the propensity of vitamin D₃ and its analogs to increase the levels of serum calcium has so far precluded their use in cancer patients except for limited clinical trials. This article summarizes the range of compounds that have been shown to increase the differentiation-inducing and antiproliferative activities of vitamin D₃ and its analogs, and discusses the possible mechanistic basis for this synergy in several selected combinations. The agents discussed include those that have differentiation-inducing activity of their own that is increased by combination with vitamin D₃ or analogs, such as retinoids or transforming growth factor-β and plant-derived compounds and antioxidants, such as curcumin and carnosic acid. Among other compounds discussed here are dexamethasone, nonsteroidal anti-inflammatory drugs, and inhibitors of cytochrome P450 enzymes, for example, ketoconazole. Thus, recent data illustrate that there are extensive, but largely unexplored, opportunities to develop combinatorial, differentiation-based approaches to chemoprevention and chemotherapy of human cancer.