Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention

Abstract

Exemestane (6-methyleneandrosta-1,4-diene-3,17-dione) is a synthetic steroidal inhibitor of the aromatase reaction that catalyzes the terminal and rate-limiting step of the biosynthesis of estrogens. It is active clinically in preventing, delaying progression of, and treating mammary cancers, many of which are estrogen receptor-positive. A striking feature of the structure of exemestane is an extended system of conjugated Michael reaction functions, which is also characteristic of inducers of a broad network of chemoprotective genes regulated by the Keap1 (Kelch-like ECAassociated protein)/Nrf2 (nuclear factor E2-related factor 2)/ARE (antioxidant response element) signaling system. These genes are largely involved in xenobiotic metabolism and antioxidative and anti-inflammatory protection, as well as the synthesis and reduction of glutathione. We show here that exemestane transcriptionally activates NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), typical chemoprotective gene products, in a wide variety of mouse, rat, and human cells. It protects several cell lines against oxidative toxicity of tert-butyl hydroperoxide and 4-hydroxynonenal, against free radical damage arising from hypoxia-reoxygenation, and against UVA radiation damage. Exemestane also inhibits the inflammatory increases in inducible nitric oxide synthase (iNOS) in mouse macrophages exposed to LPS (lipopolysaccharide), thereby resembling the isothiocyanate sulforaphane derived from broccoli. Remarkably, combinations of exemestane and sulforaphane act highly synergistically, and this property is also displayed by several other phytochemicals. Thus, exemestane has a wide range of previously unrecognized protective activities, probably unrelated to aromatase inhibition. Its potential for reducing the risk, not only of breast cancer, but also of other chronic diseases that arise from inflammation, oxidative stress, and DNA-damaging electrophiles, requires exploration, particularly in view of the synergism with other phytochemicals.

A Glance at… Broccoli, glucoraphanin, and sulforaphane

“…Sulforaphane also exhibits anti-inflammatory properties. For example, free sulforaphane has exhibited concentrationdependent attenuation of bacterial lipopolysaccharide-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and synthesis and secretion of proinflammatory cytokines [69,70]. In a model of osteoarthritis, sulforaphane has attenuated interleukin (IL)-1b potentiation of the expression of tissue-degrading A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS4) (aggrecanase-1), ADAMTS5 (aggrecanase-2), matrix metalloproteinase (MMP)-1, and MMP13 in primary human articular chondrocytes following sulforaphane uptake into these cells [71].…”

TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione

“…Exogenous compounds, including allyl isothiocyanate (AITC), and endogenously generated reactive oxygen species (ROS) and their derivatives, have been identified as TRPA1 agonists (9)(10)(11)(12). Similar to other reactive agonists (7), highly electrophilic conjugated Michael acceptor groups of exemestane (13) and nitrile moieties of letrozole and anastrozole (14) react with the thiol groups of specific cysteine and lysine residues to trigger TRPA1 and activate nociceptors (8).…”

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

“…Other studies utilizing cell culture models revealed a synergism between sulforaphane and modulators of estrogen receptor signaling including 17β-Estradiol and exemestane, an aromatase inhibitor, although the underlying mechanism(s)remain(s) undefined (Angeloni et al, 2017, Liu and Talalay, 2013). Since ER-β reportedly exerts a positive impact on NRF2 signaling, we performed topical treatments of SF in combination with pre-treatment intra-peritoneal injections of diarylpropionitrile (DPN), an ER-β selective agonist that has been shown to also oppose ER-α activity (Song and Pan, 2012).…”