Epigenetics/Epigenomics and Prevention of Early Stages of Cancer by Isothiocyanates

Abstract

Cancer is a complex disease and cancer development takes 10-50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive "epigenetic modifiers" involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models. This review summarizes the latest advances on the role of epigenetics/epigenomics by isothiocyanates in prevention of skin, colon, lung, breast, and prostate cancers. The exact molecular mechanism how isothiocyanates modify the epigenetic/epigenomic machinery is unclear. We postulate "redox" processes would play important roles. In addition, isothiocyanates sulforaphane and phenethyl isothiocyanate, possess multifaceted molecular mechanisms would be considered as "general" cancer preventive agents not unlike chemotherapeutic agents like platinum-based or taxane-based drugs. Analogous to chemotherapeutic agents, the isothiocyanates would need to be used in combination with other nontoxic chemopreventive phytochemicals or drugs such as NSAIDs, 5-α-reductase/aromatase inhibitors targeting different signaling pathways would be logical for the prevention of progression of tumors to late advanced metastatic states.

Figure 1

Schematic representation of epigenetic pathways in stepwise carcinogenesis process and chemopreventive effects of isothiocyanates (ITCs) impinging upon and integrating with the cellular processes during cancer development. Major epigenetic mechanism involved (A) Histone modification, (B) DNA modifications, and (C) miRNA regulation. The role of ITCs in modifying/reversing of these epigenetic mechanisms and signaling pathways including reactive oxygen/nitrogen species (RO/NS), xenobiotic metabolizing enzymes (XMEs), DNA damage/repair, cellular kinases, onco/proto-oncogenes, inflammatory, matrix metalloproteinases (MMPs), epithelial-mesenchymal transition (EMT) biomarkers, and immune suppression, among others, in the process of carcinogenesis viz. initiation, promotion and progression. (↑ activation, ↓ inhibition, ⊥ blocking)