Targeting Cytochrome P450 Enzymes: A New Approach in Anticancer Drug Development

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.

Phytochemical investigation of Tunisian Salicornia herbacea L., antioxidant, antimicrobial and cytochrome P450 (CYPs) inhibitory activities of its methanol extract

“…Members of this family are under the transcriptional regulation of the aryl hydrocarbon receptor (AhR), and are known to activate pro-carcinogens such as polycyclic aromatic hydrocarbons (PAHs) (Bruno & Njar, 2007). Fig.…”

“…CYP activation of certain anticancer drugs has long been known and the importance of this process as a way of targeting novel anticancer therapy is being explored. However, certain CYPs involved in hormone and vitamin metabolisms and in metabolic activation of genotoxic substances were reported to play important roles in tumour formation and development (Bruno & Njar, 2007).…”

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

“…Based on this hypothesis, agents that inhibit RA clearance have been developed, collectively called RAMBAs (retinoic acid metabolism blocking agents). There have been various other reviews on RAMBAs that are excellent resources on the chemistry and synthesis of these inhibitors [80–82]. The remainder of this review will primarily focus on the pharmacological effects and clinical results of both older and more recently developed RAMBAs.…”

Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: Situación actual y perspectivas terapéuticas

“…Este fármaco es metabolizado principalmente por las enzimas CYP2C8 y CYP3A4, y sus principales productos metabólicos son: 6α−hidroxipaclitaxel y 3'hidroxipaclitaxel, La enzima CYP2C8 cataliza la reacción que tiene como producto 6α−hidroxipaclitaxel y la enzima CYP3A4 cataliza la reacción que tiene como producto 3'hydroxipaclitaxel (Figura 1). El 6α−hidroxipaclitaxel 30 veces menos citotóxico que el paclitaxel 2,3,5 . Una situación similar se evidencia en el metabolismo del docetaxel, comúnmente utilizado contra varios tipos de tumores, incluyendo cáncer de ovario, mama y pulmón, su efecto antitumoral es similar al del paclitaxel, aunque es considerado mejor inhibidor de la división celular.…”

“…De esta manera, algunos individuos responden mejor al tratamiento antitumoral, dependiendo de si se produce una mayor o menor cantidad de enzimas P450 específicas en sus organismos y de si el sustrato que se metaboliza es activo por sí mismo o si, por el contrario, se activa a través de la reacción catalizada por la enzima P450. Según el consenso general, las dos principales causas que provocan la variación interindividual del metabolismo de los fármacos son: los polimorfismos genéticos y la inducción o inhibición enzimática debida al suministro concomitante de otros fármacos, factores ambientales o al mismo sustrato 4,5 .…”