Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research.
Inverse association between dietary intake of cruciferous vegetables and cancer risk observed in population-based case-control studies is partly attributable to structurally simple but mechanistically complex phytochemicals with an isothiocyanate (-N=C=S) functional group. Cancer protective role for dietary isothiocyanates (ITCs) is substantiated by preclinical studies in rodent models. A common feature of many naturally occurring ITCs relates to their ability to cause growth arrest and cell death selectively in cancer cells. At the same time, evidence continues to accumulate to suggest that even subtle change in chemical structure of the ITCs can have a profound effect on their activity and mechanism of action. Existing mechanistic paradigm stipulates that ITCs may not only prevent cancer initiation by altering carcinogen metabolism but also inhibit post-initiation cancer development by suppressing many processes relevant to tumor progression, including cellular proliferation, neoangiogenesis, epithelial-mesenchymal transition, and self-renewal of cancer stem cells. Moreover, the ITCs are known to suppress diverse oncogenic signaling pathways often hyperactive in human cancers (e.g. nuclear factor-κB, hormone receptors, signal transducer and activator of transcription 3) to elicit cancer chemopreventive response. However, more recent studies highlight potential adverse effect of Notch activation by ITCs on their ability to inhibit migration of cancer cells. Mechanisms underlying ITC-mediated modulation of carcinogen metabolism, growth arrest, and cell death have been reviewed extensively. This article provides a perspective on bench-cage-bedside evidence supporting cancer chemopreventive role for some of the most promising ITCs. Structure-activity relationship and mechanistic complexity in the context of cancer chemoprevention with ITCs is also highlighted.
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. singhs@upmc.edu
Shivendra V
SV
Singh
Kamayani
K
Singh
D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000032:analysis; D018890:Chemoprevention; D004032:Diet; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D057170:Translational Research, Biomedical; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced; D014675:Vegetables / Q000737:chemistry*
D015415:Biomarkers; D017879:Isothiocyanates; D012333:RNA, Messenger