Cytochrome p450 retinoic acid 4-hydroxylase inhibitors: potential agents for cancer therapy

Retinoids play a crucial role in cellular differentiation and proliferation of epithelial tissue and their utility in oncology and dermatology is well documented. This mini review focuses on the role of all-trans-retinoic acid (ATRA or RA), the principal endogenous retinoid and its metabolism in cancer therapy. ATRA has been used successfully in differentiating therapy of acute promyelecytic leukemia and other types of cancers. However, its usefulness is limited by the rapid emergence of ATRA resistance due (in part) to ATRA - induced acceleration of ATRA metabolism. A novel strategy to subjugate the limitation associated with exogenous ATRA therapy has been to modulate and/or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzyme(s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis and evaluation of RAMBAs since 1987. Major emphasis is given to liarozole, the most studied and only RAMBA to undergo clinical investigation and also the recently developed novel and highly potent 4-azoly retinoids. The potential role of a new family of cytochrome P450 enzymes, CYP26, with specificity towards ATRA is also discussed.