Associate Editor: V. Schini-Kerth Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis Nam Joo Kang a,1 , Seung Ho Shin b,c,1 , Hyong Joo Lee c , Ki Won Lee b,c, ⁎ a School of Applied Biosciences, Kyungpook National University, Daegu, Republic of Korea b Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea c Department of Agricultural Biotechnology, Center for Agricultural Biomaterials, and Research Institute for Agriculture and Life Science, Seoul National University, Seoul, Republic of Korea abstract article info Keywords: Carcinogenesis Chemoprevention Polyphenol Signaling cascades 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. © 2011 Elsevier Inc. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 2. Importance of polyphenols in chemoprevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 3. Tumor promotion stage as a key process for chemoprevention with polyphenols . . . . . . . . . . . . . 311 4. Signaling cascades as possible molecular targets of chemoprevention with polyphenols . . . . . . . . . 311 5. Polyphenols as direct signaling regulators in carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . 311 6. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Pharmacology & Therapeutics 130 (2011) 310–324 Abbreviations: 5-DK, 5-Deoxykaempferol; 7,3′,4′-THIF, 7,3′,4′-Trihydroxyisoflavone; AhR, aryl hydrocarbon receptor; AP-1, activator protein 1; CAPE, caffeic acid phenethyl ester; CBP, CREB-binding protein; CDK, cyclin-dependent kinase; COX, cyclooxygenase; EGCG, (-)-Epigallocatechin gallate; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; G3BP1, Ras-GTPase-activating protein SH3 domain-binding protein 1; GRP78, 78 kDa glucose-regulated protein; HAT, histone acetyltransferase; Hsp90, heat shock protein 90; IGF-IR, Insulin-like growth factor-I receptor; IKK, IκB kinase; IL, interleukin; IκB, inhibitor kappaB; iNOS, inducible nitric oxide synthase; JAK, janus kinase 1; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein-ERK kinase; MGMT, O 6 -methylguanine DNA methyltransferase; MKK, mitogen-activated protein kinase kinase; NF, nuclear factor; PI3-K, phosphatidylinositol-3-kinase; ROS, reactive oxygen species; RSK, ribosomal S6 kinase; SFK, Src family kinase; STAT, signal transducer and activator of transcription; Syk, spleen tyrosine kinase; TNF, tumor necrosis factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; UV, ultraviolet; ZAP-70, zeta-chain-associated protein kinase 70. ⁎ Corresponding author at: Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Tel.: +82 2 456 6178; fax: +82 2 3436 6178. E-mail address: kiwon@konkuk.ac.kr (K.W. Lee). 1 Nam Joo Kang and Seung Ho Shin contributed equally to this work. 314 316 322 322 322 0163-7258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2011.02.004 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera