Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy

Abstract

The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed.

Fig. 1.

Chemical structures of CYP17 inhibitors: ketoconazole (1), abiraterone (2), and VN/124-1 (TOK-001) (3).

Fig. 2.

VN/124-1's mechanisms of action by concentration.

Fig. 3.

Schematic representation of androgen-dependent and androgen-independent mechanisms of action of VN/124-1.

Fig. 4.

Transplacental lymphoma mortality and fetal Cyp1b1 genotype. [Reproduced from Castro DJ, Baird WM, Pereira CB, Giovanini J, Lohr CV, Fischer KA, Yu Z, Gonzalez FJ, Krueger SK, and Williams DE (2008) Fetal mouse Cyp1b1 and transplacental carcinogenesis from maternal exposure to dibenzo(a,l)pyrene. Cancer Prev Res (Phila Pa) 1:128–134. Copyright © 2008 American Association for Cancer Research. Used with permission.]

Fig. 5.

In dams heterozygous for responsive and nonresponsive versions of the AHR receptor (AHR^b-1/d), exposure to indole-3-carbinol in the maternal diet protects the offspring from transplacental DBP mortality. [The figure has been drawn on the basis of the findings in Yu et al. (2006b).]

Fig. 6.

Schematic representation of Nrf2-dependent modulation of phase II, inflammatory, and antioxidant enzymes by nutritional phytochemicals. HO-1, heme-oxygenase-1; NQO1, NAD(P)H-quinone reductase-1; UGT, UDP-glucuronosyltransferase 1A1; GST, glutathione S-transferase μ-1; COX-2, cyclooxygenase 2; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; MRP1, multidrug resistance protein 1.

Fig. 7.

Retroviral delivery of CYP2B6 versus CYP2B11: evaluation of CYPA cytotoxicity.

Fig. 8.

Tumor-cell cytotoxicity of CYP3A4-activated MMDX. A, MMDX cytotoxicity. B, incomplete Freund's adjuvant (IFA) cytotoxicity. C, reversal by CYP3A inhibitors. [The figure has been drawn on the basis of the findings in Lu et al., 2009.]