1560 Review Potential of Spice-Derived Phytochemicals for Cancer Prevention Author Bharat B. Aggarwal, Ajaikumar B. Kunnumakkara, Kuzhuvelil B. Harikumar, Sheeja T. Tharakan, Bokyung Sung, Preetha Anand Affiliation Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Key Words Abstract GA: gambogic acid ●" spice ! GSH: glutathione ●" cancer Although spices have been used for thousands of GST: glutathione S-transferase ●" chemoprevention years and are known for their flavor, taste and col- H2O2: hydrogen peroxide ●" phytochemicals or in the food, they are not usually recognized for hTERT: human telomerase reverse ●" molecular targets their medicinal value. Extensive research within transcriptase the last two decades from our laboratory and oth- ICAM-1: intercellular adhesion molecule-1 ers has indicated that there are phytochemicals IKK: IκBα kinase present in spices that may prevent various chronic IL: interleukins illnesses including cancerous, diabetic, cardiovas- JAK: Janus kinases cular, pulmonary, neurological and autoimmune 5-LOX: 5-lipoxygenase diseases. For instance, the potential of turmeric MM: multiple myeloma (curcumin), red chilli (capsaicin), cloves (euge- MMP: matrix metalloproteinase nol), ginger (zerumbone), fennel (anethole), ko- NADH: nicotinamide adenine dinucleotide kum (gambogic acid), fenugreek (diosgenin), and hydride black cumin (thymoquinone) in cancer prevention NF-κB: nuclear factor kappa B has been established. Additionally, the mecha- NIK: NF-κB inducing kinase nism by which these agents mediate anticancer NNK: nitrosamine 4-(methylnitrosamino)- effects is also becoming increasingly evident. The 1-(3-pyridyl)-1-butanone received April 10, 2008 current review describes the active components RANKL: receptor activator for nuclear factor accepted May 6, 2008 of some of the major spices, their mechanisms of κB ligand Bibliography action and their potential in cancer prevention. RHD: Rel homology domain DOI 10.1055/s-2008-1074578 RTX: resiniferatoxin Planta Med 2008; 74: 1560– Abbreviations STAT: signal transducer and activator of 1569 ! transcription © Georg Thieme Verlag KG ADT: anethole ditholethione TNF: tumor necrosis factor Stuttgart · New York Bcl-3: B cell lymphoma protein-3 TNFR: TNF receptor This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Published online July 8, 2008 ISSN 0032-0943 CDK7: cyclin-dependent kinase 7 TQ: thymoquinone cIAP: inhibitor of apoptosis TRAF: TNF receptor associated factor Correspondence COX-2: cyclooxygenase-2 uPA: urokinase plasminogen activator Bharat B. Aggarwal, PhD DNA: deoxyribonucleic acid VCAM: vascular cell adhesion molecule Cytokine Research Laboratory EGF: epidermal growth factor VEGF: vascular endothelial growth factor Department of Experimental Therapeutics ELAM-1: endothelial leukocyte adhesion VEGFR2: VEGF receptor 2 The University of Texas molecule-1 M. D. Anderson Cancer Center ERK or Erk: extracellular signal-regulated 1515 Holcombe Boulevard kinases Box 143 Houston Texas 77030 Introduction more than 90% of the cancers are preventable. USA ! Tel.: +1/713/794/1817 Cigarette smoke, alcohol, environmental pollu- Fax: +1/713/745/6339 It is generally believed that prevention is better tion, sunlight and diet have been shown to play [email protected] than treatment. It is also an accepted reality that a major role in causing cancer. How these agents Aggarwal BBet al. Potential of Spice-Derived… Planta Med 2008; 74: 1560– 1569 Review 1561 cause cancer is also becoming evident. One of the major media- EGF, and other growth factors; constitutive activation of STAT3 tors of cancer that has emerged within last five years is chronic has been discovered in a wide variety of tumors. inflammation [1]. In contrast to acute inflammation, chronic in- Dietary agents have been linked with prevention and therapy of flammation is a low level inflammation that can persist over cancer through a mechanism that is not well understood. We 20– 30 years; thus eventually leading to cancer. Perhaps the postulated that inflammation plays a major role in tumorigene- best-known markers of chronic inflammation include inflam- sis through the activation of NF-κB and STAT3 [1]. We also matory cytokines [such as tumor necrosis factor (TNF), receptor postulated that dietary agents mediate their effect through mod- activator for nuclear factor κ B ligand (RANKL), interleukins (IL-1, ulation of NF-κB and STAT-3 activation [4]. This factor regulates IL-6, IL-8)] and chemokines, inflammatory enzymes [cyclooxy- the expression of various genes that control apoptosis, viral rep- genase-2 (COX-2), 5-lipoxygenase (5-LOX), matrix metallopro- lication, tumorigenesis, various autoimmune diseases, and in- teinase (MMP) and urokinase plasminogen activator (uPA)], ad- flammation. NF-κB has been linked to the development of carci- hesion molecules [intercellular adhesion molecule-1 (ICAM-1)], nogenesis for several reasons. Firstly, various carcinogens and vascular cell adhesion molecule (VCAM-1), endothelial leuko- tumor promoters have been shown to activate NF-κB. Secondly, cyte adhesion molecule-1 (ELAM-1), and certain growth factors activation of NF-κB has been shown to block apoptosis and pro- such as epidermal growth factor (EGF). Interestingly, all the me- mote proliferation. Thirdly, the tumor microenvironment can in- diators of inflammation are primarily regulated by two different duce NF-κB activation. Fourthly, constitutive expression of NF- transcription factors, nuclear factor kappa B (NF-κB) and signal κB is frequently found in tumor cells. Fifthly, NF-κB activation in- transducer and activator of transcription-3 (STAT-3). duces resistance to chemotherapeutic agents. Sixthly, several The process of tumorigenesis requires cellular transformation, genes involved in tumor initiation, promotion, and metastasis hyper-proliferation, invasion, angiogenesis, and metastasis. Sev- are regulated by NF-κB. Seventhly, various chemopreventive eral genes that mediate these processes are regulated by the agents have been found to down-regulate the NF-κB activation. transcription factor NF-κB. The latter is activated by various car- All these observation suggest that NF-κB could mediate tumori- cinogens, inflammatory agents, and tumor promoters. Thus, genesis and thus can be used as a target for chemoprevention agents which can suppress NF-κB activation have the potential and for the treatment of cancer. Besides NF-κB, we have also tar- to suppress carcinogenesis. NF-κB is a ubiquitous transcription geted STAT3, another transcription factor that mediates tumor- factor that binds to a specific deoxyribonucleic acid (DNA) se- ienesis. The evidence below shows that phytochemicals derived quence as a dimeric complex composed of various combinations from spices are important inhibitors of NF-κB and STAT3 activa- of members of the Rel/NF-κB family of polypeptides [2]. Family tion, and can suppress the expression of genes involved in carci- members of this transcription factor are 35 to 61 % homologous nogenesis and tumorigenesis in vivo. to each other and have a Rel homology domain (RHD) of about 300 amino acids. NF-κB proteins are present in the cytoplasm of all cells, where they are kept in an inactive state by a family of Evidence That Spice-Derived Phytochemicals can anchorin domain-containing proteins, which includes IκBα, Mediate Cancer Prevention IκBβ,IκBγ,IκBε, B cell lymphoma protein-3 (Bcl-3), p105, and ! p100. Under resting conditions, NF-κB consists of a heterotrimer Phytochemicals derived from numerous spices have been linked of p50, p65, and IκBα in the cytoplasm; only upon activation, do with cancer prevention. This review, however, will focus on the p50 and p65 subunits translocate to the nucleus leading to some of the major spice-derived phytochemicals as chemopre- the sequence of events. Most carcinogens, inflammatory agents, ventive agents (●" Fig. 1). and tumor promoters, including cigarette smoke, phorbol ester, okadaic acid, hydrogen peroxide (H2O2), and TNF, have been Capsaicin (red chilli) shown to activate NF-κB. The activation of NF-κB involves the Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a princi- phosphorylation, ubiquitination and degradation of IκBα and pal pungent ingredient of hot and red chili peppers that belong phosphorylation of p65, which, in turn, leads to the transloca- to the plant genus Capsicum (Solanaceae). In addition to alleviat- tion of NF-κB to the nucleus where it binds to specific response ing neuropathic pain and itching in humans, capsaicin has ex- elements in the DNA. The phosphorylation of IκBα is catalyzed hibited anticancer effects in animal models, suppressing carci- by IκBα kinase (IKK), which is essential for NF-κB activation by nogenesis of the skin, colon, lung, tongue, and prostate. The most agents. NF-κB has been shown to regulate the expression mechanism by which this vanilloid mediates its anticarcinogen- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. of several genes whose products are involved in tumorigenesis. ic effects is not understood but it has been shown to alter the These include antiapoptotic genes [e.g., inhibitor of apoptosis metabolism of carcinogens such as aflatoxin B1 and the tobac- (cIAP), survivin, TNF receptor associated factor (TRAF), Bcl-2, co-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)- and Bcl-xL],