Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis

Multiple lines of evidences suggest that oxidative stress induced by reactive oxygen species are closely related to multi-stage carcinogenesis. Polyphenols, a group of chemicals with more than one phenol unit or building block per molecule, have been recognized for possessing many health benefits including cancer-preventive effects mainly due to their antioxidant activity. However, polyphenols can directly bind with signaling molecules involved in carcinogenesis and regulate its activity. Moreover, it is noteworthy that the binding between the polyphenol and the target protein is determined by their structural relationship, which implies that different polyphenols have different target proteins, leading to divergent chemopreventive effects. Extracellular stimuli transmit signals into a cell by activating their target signaling cascades involved in carcinogenesis. As an example, Src family kinase, a family of proto-oncogenic tyrosine kinases activated by a variety of oxidative stress and proinflammatory agents, is known to regulate cell proliferation, differentiation, survival and angiogenesis. Src family kinase subsequently activates downstream signal cascades including mitogen-activated protein kinase, phosphoinositol-3-kinase, and nuclear factor-kappaB, thereby inducing cell proliferation and causing cancer. Recent studies demonstrate that polyphenols can directly target signaling cascades involved in inflammation and the development of cancer. Inhibition of the kinases by polyphenols contributes to the attenuation of carcinogenesis. Therefore, the development of polyphenols as direct inhibitors against target proteins is regarded as a rational approach for chemoprevention. This review describes and discusses recent results about the direct interactions of polyphenols and protein kinases in cancer chemoprevention.