Plant phenolics regulate neoplastic cell growth and survival: a quantitative structure-activity and biochemical analysis.

The anti-tumour activities of many plant phenolics at high concentrations (>100 micromol/L) suggest their potential use as dietary supplements in cancer chemoprevention and cancer chemotherapy. However, it is not clear what impact phenolic compounds have at the physiological concentrations obtained through consumption of high phenolic diets on neoplastic cells. In the present study, 54 naturally occurring phenolics were evaluated at physiologically relevant concentrations for their capacity to alter PC12 cell viability in response to serum deprivation, the chemotherepeutic agent etoposide, and the apoptogen C2-ceramide. Surprisingly, novel mitogenic, cytoprotective, and antiapoptotic activities were detected. Quantitative structure-activity relationship modelling indicated that many of these activities could be predicted by compound lipophilicity, steric bulk, and (or) antioxidant capacity, with the exception of inhibition of ceramide-induced apoptosis. Where quantitative structure-activity relationship analysis was insufficient, biochemical assessment demonstrated that the benzoate orsellinic acid blocked downstream caspase-12 activation following ceramide challenge. These findings demonstrate substantive mitogenic, cytoprotective, and antiapoptotic biological activities of plant phenolics on neoplastic cells at physiologically relevant dietary concentrations that should be considered in chemopreventive and chemotherapeutic strategies.