Chemopreventive herbal anti-oxidants: current status and future perspectives

Abstract

Cancer chemoprevention is fast becoming a lucrative approach for controlling cancer. Carcinogenesis being a complex multi-step, multi-factorial process, a number of chemopreventive interventions can be employed. These strategies are generally directed against two broad events of carcinogenesis viz., initiation and promotion/progression. Anti-initiation interventions principally involve inhibition of carcinogen activation, scavenging of free radicals and reactive carcinogen metabolites along with enhanced detoxification of carcinogens by modulating cellular metabolism. Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation. Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents. These agents after emerging successful through a series of in vitro and in vivo assays enter clinical trials. Many dietary compounds have emerged as promising chemopreventive agents in empirical experiments. However, in clinical trials these compounds have met with limited success. This emphasizes the need for further detailed research on the mechanisms of observed chemoprevention and choice, dose, duration and bioavailability of chemopreventive agent used. Complex issues such as choice and nutritional status of target population, genetic variation, gene-environment interactions and relevance of biomarkers analyzed also warrant further research and analyses.

Keywords: carcinogenesis; chemoprevention; current status; herbal antioxidant; screening assays.

Fig. 1

Chemopreventive agents can prevent cancer by inhibiting the process of carcinogenesis either by inhibiting initiation and/or promotion event.

Fig. 2

Schematic presentations of steps where chemopreventive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initiation by inhibiting xenobiotic induced transcriptional upregulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (exogenous/endogenous); XRE = xenobiotic response element; C = chemopreventive agent.

Fig. 3

Model representing putative signaling cascade modulated by chemopreventive agents for induction of phase II enzymes. ROS modulation brought about by chemopreventive agents activate signaling kinases which modify NRF2. Modified NRF2 dissociates from its inhibitor keap1 and translocates to nucleus where it heterodimerizes with other transcription factors and binds to ARE, transactivating down stream genes.

Fig. 4

Schematic presentations of signaling cascade where chemopreventive agents act as a suppressor. Chemopreventive agent can act as a suppressor either by inhibiting signaling kinases that activate transcription factor like AP-1 and NF-kB which in turn activate cell proliferation genes or by inducing apoptosis via activation of proapoptotic proteins like bax. C = chemopreventive agent; wt = wild type.