Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, over-activation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.

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Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents.

Purpose: The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism. Experimental Design: Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro . A nonobese diabetic/severe combined immunodeficient xenograft model was used to determine whether sulforaphane could target breast CSCs in vivo , as assessed by Aldefluor assay, and tumor growth upon cell reimplantation in secondary mice. The potential mechanism was investigated using Western blotting analysis and β-catenin reporter assay. Results: Sulforaphane (1-5 μmol/L) decreased aldehyde dehydrogenase–positive cell population by 65% to 80% in human breast cancer cells ( P P 50% in nonobese diabetic/severe combined immunodeficient xenograft tumors ( P = 0.003). Sulforaphane eliminated breast CSCs in vivo , thereby abrogating tumor growth after the reimplantation of primary tumor cells into the secondary mice ( P Conclusions: Sulforaphane inhibits breast CSCs and downregulates the Wnt/β-catenin self-renewal pathway. These findings support the use of sulforaphane for the chemoprevention of breast cancer stem cells and warrant further clinical evaluation. Clin Cancer Res; 16(9); 2580–90. ©2010 AACR.

https://clincancerres.aacrjournals.org/content/clincanres/16/9/2580.full.pdf

Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells

Globally cancer is a disease which severely effects the human population. There is a constant demand for new therapies to treat and prevent this life-threatening disease. Scientific and research interest is drawing its attention towards naturally-derived compounds as they are considered to have less toxic side effects compared to current treatments such as chemotherapy. The Plant Kingdom produces naturally occurring secondary metabolites which are being investigated for their anticancer activities leading to the development of new clinical drugs. With the success of these compounds that have been developed into staple drugs for cancer treatment new technologies are emerging to develop the area further. New technologies include nanoparticles for nano-medicines which aim to enhance anticancer activities of plant-derived drugs by controlling the release of the compound and investigating new methods for administration. This review discusses the demand for naturally-derived compounds from medicinal plants and their properties which make them targets for potential anticancer treatments.

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Medicinal Plants: Their Use in Anticancer Treatment.

Multi-targeted prevention of cancer by sulforaphane.

Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment

Consumers of higher levels of Brassica vegetables, particularly those of the genus Brassica (broccoli, Brussels sprouts and cabbage), reduce their susceptibility to cancer at a variety of organ sites. Brassica vegetables contain high concentrations of glucosinolates that can be hydrolyzed by the plant enzyme, myrosinase, or intestinal microflora to isothiocyanates, potent inducers of cytoprotective enzymes and inhibitors of carcinogenesis. Oral administration of either the isothiocyanate, sulforaphane, or its glucosinolate precursor, glucoraphanin, inhibits mammary carcinogenesis in rats treated with 7,12-dimethylbenz[a]anthracene. In this study, we sought to determine whether sulforaphane exerts a direct chemopreventive action on animal and human mammary tissue. The pharmacokinetics and pharmacodynamics of a single 150 mmol oral dose of sulforaphane were evaluated in the rat mammary gland. We detected sulforaphane metabolites at concentrations known to alter gene expression in cell culture. Elevated cytoprotective NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) gene transcripts were measured using quantitative real-time polymerase chain reaction. An observed 3-fold increase in NQO1 enzymatic activity, as well as 4-fold elevated immunostaining of HO-1 in rat mammary epithelium, provides strong evidence of a pronounced pharmacodynamic action of sulforaphane. In a subsequent pilot study, eight healthy women undergoing reduction mammoplasty were given a single dose of a broccoli sprout preparation containing 200 mmol of sulforaphane. Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells. These findings provide a strong rationale for evaluating the protective effects of a broccoli sprout preparation in clinical trials of women at risk for breast cancer.

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Melanie Erb

Papers

Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast