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Targeting cytochrome P450 enzymes: a new approach in anti-cancer drug development
Robert D Bruno1, Vincent C O Njar
1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
Abstract:
Cytochrome P450s (CYPs) represent a large class of heme-containing enzymes that catalyze the metabolism of multitudes of substrates both endogenous and exogenous. Until recently, however, CYPs have been largely overlooked in cancer drug development, acknowledged only for their role in phase I metabolism of chemotherapeutics. The first successful strategy targeting CYP enzymes in cancer therapy was the development of potent inhibitors of CYP19 (aromatase) for the treatment of breast cancer. Aromatase inhibitors ushered in a new era in hormone ablation therapy for estrogen dependent cancers, and have paved the way for similar strategies (i.e., inhibition of CYP17) that combat androgen dependent prostate cancer. Identification of CYPs involved in the inactivation of anti-cancer metabolites of vitamin D(3) and vitamin A has triggered development of agents that target these enzymes as well. The discovery of the over-expression of exogenous metabolizing CYPs, such as CYP1B1, in cancer cells has roused interest in the development of inhibitors for chemoprevention and of prodrugs designed to be activated by CYPs only in cancer cells. Finally, the expression of CYPs within tumors has been utilized in the development of bioreductive molecules that are activated by CYPs only under hypoxic conditions. This review offers the first comprehensive analysis of strategies in drug development that either inhibit or exploit CYP enzymes for the treatment of cancer.
Insights
Cytochrome P450s (CYPs) are crucial in cancer drug development. New strategies target CYPs to inhibit cancer growth or activate anti-cancer drugs specifically within tumors.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Cytochrome P450s (CYPs) are heme-containing enzymes involved in metabolizing various substrates.
- CYPs were historically underutilized in cancer drug development, primarily noted for chemotherapeutic metabolism.
- Recent advances highlight CYPs' potential in novel cancer therapies.
Purpose of the Study:
- To provide a comprehensive review of drug development strategies targeting Cytochrome P450 enzymes in cancer treatment.
- To explore both inhibitory and exploitative approaches utilizing CYPs in oncology.
Main Methods:
- Review of existing literature on Cytochrome P450 enzymes in cancer therapy.
- Analysis of strategies involving CYP inhibition (e.g., CYP19, CYP17).
- Examination of approaches exploiting CYP overexpression or activity in cancer cells (e.g., prodrug activation, bioreductive agents).
Main Results:
- CYP19 (aromatase) inhibitors are effective in treating estrogen-dependent breast cancer.
- CYP17 inhibitors show promise for androgen-dependent prostate cancer.
- Targeting CYPs involved in vitamin D(3) and vitamin A metabolism is under development.
- Overexpressed CYPs (e.g., CYP1B1) in cancer cells are targets for chemoprevention and prodrug activation.
- Tumor-expressed CYPs are utilized for activating bioreductive prodrugs under hypoxic conditions.
Conclusions:
- Cytochrome P450 enzymes represent a versatile target class for innovative cancer drug development.
- Strategies include direct inhibition, exploiting cancer-specific CYP activity, and prodrug activation.
- Targeting CYPs offers promising avenues for hormone-dependent cancers, chemoprevention, and targeted therapies.
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