Cancer Prevention with Natural Ingredients

Potential of spice-derived phytochemicals for cancer prevention.

Aggarwal BB, Kunnumakkara AB, Harikumar KB, Tharakan ST, Sung B, Anand P. Planta Med. 2008 Oct;74(13):1560-9. Epub 2008 Jul 8.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. aggarwal@mdanderson.org

Although spices have been used for thousands of years and are known for their flavor, taste and color in the food, they are not usually recognized for their medicinal value. Extensive research within the last two decades from our laboratory and others has indicated that there are phytochemicals present in spices that may prevent various chronic illnesses including cancerous, diabetic, cardiovascular, pulmonary, neurological and autoimmune diseases. For instance, the potential of turmeric (curcumin), red chilli (capsaicin), cloves (eugenol), ginger (zerumbone), fennel (anethole), kokum (gambogic acid), fenugreek (diosgenin), and black cumin (thymoquinone) in cancer prevention has been established. Additionally, the mechanism by which these agents mediate anticancer effects is also becoming increasingly evident. The current review describes the active components of some of the major spices, their mechanisms of action and their potential in cancer prevention.

Synergistic effects of multiple natural products in pancreatic cancer cells.

Wang Z, Desmoulin S, Banerjee S, Kong D, Li Y, Deraniyagala RL, Abbruzzese J, Sarkar FH. Life Sci. 2008 Aug 15;83(7-8):293-300. Epub 2008 Jun 28. Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States.

Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC.

Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-kappaB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways.

Multitargeted therapy of cancer by silymarin.

Ramasamy K, Agarwal R. Cancer Lett. 2008 Oct 8;269(2):352-62. Epub 2008 May 9.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.

Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention.

Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.

Vitamin D and sunlight: strategies for cancer prevention and other health benefits.

Holick MF. Clin J Am Soc Nephrol. 2008 Sep;3(5):1548-54. Epub 2008 Jun 11.
Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts, USA. mfholick@bu.edu

Vitamin D deficiency is a worldwide health problem. The major source of vitamin D for most humans is sensible sun exposure. Factors that influence cutaneous vitamin D production include sunscreen use, skin pigmentation, time of day, season of the year, latitude, and aging.

Serum 25-hydroxyvitamin D [25(OH)D] is the measure for vitamin D status. A total of 100 IU of vitamin D raises blood level of 25(OH)D by 1 ng/ml. Thus, children and adults who do not receive adequate vitamin D from sun exposure need at least 1000 IU/d vitamin D.

Lack of sun exposure and vitamin D deficiency have been linked to many serious chronic diseases, including autoimmune diseases, infectious diseases, cardiovascular disease, and deadly cancers. It is estimated that there is a 30 to 50% reduction in risk for developing colorectal, breast, and prostate cancer by either increasing vitamin D intake to least 1000 IU/d vitamin D or increasing sun exposure to raise blood levels of 25(OH)D >30 ng/ml.

women who are vitamin D deficient have a 253% increased risk for developing colorectal cancer.

Most tissues in the body have a vitamin D receptor. The active form of vitamin D, 1,25-dihydroxyvitamin D, is made in many different tissues, including colon, prostate, and breast. It is believed that the local production of 1,25(OH)(2)D may be responsible for the anticancer benefit of vitamin D. Recent studies suggested that women who are vitamin D deficient have a 253% increased risk for developing colorectal cancer, and women who ingested 1500 mg/d calcium and 1100 IU/d vitamin D(3) for 4 yr reduced risk for developing cancer by >60%.

Tea, Coffee and Prostate Cancer.

Protective effects of green tea against prostate cancer.

Lee AH, Fraser ML, Meng X, Binns CW. Expert Rev Anticancer Ther. 2006 Apr;6(4):507-13.
School of Public Health, Curtin University of Technology, GPO Box U 1987, Perth, WA 6845, Australia. andy.lee@curtin.edu.au

Prostate cancer has the third highest incidence of all cancers in men worldwide with incidence and mortality being particularly high in affluent, developed countries. Tea, especially green tea, has demonstrated promise in the prevention of several cancers. Green tea contains several components including catechins, a category of polyphenols that have chemopreventive properties.

Although evidence from epidemiological studies is not comprehensive, it is strengthened by animal and in vitro evidence suggesting that consumption of tea is associated with decreased risk or progression of prostate cancer. Emerging evidence and potential biological mechanisms for the role of green tea in prostate cancer prevention are presented in this review.

Tea and lycopene protect against prostate cancer.

Jian L, Lee AH, Binns CW. Asia Pac J Clin Nutr. 2007;16 Suppl 1:453-7
School of Public Health, Curtin University of Technology, GPO Box U 1987, Perth, WA 6845, Australia. L.Jian@exchange.curtin.edu.au

Prostate cancer is the most common male cancer in developed countries and is increasing in the developing world. Its long latency and geographical variation suggest the possibility of prevention or postponement of onset by dietary modification. To investigate the possible joint effect of lycopene and green tea on prostate cancer risk, a case-control study was conducted in Hangzhou, China, with 130 prostate cancer patients and 274 hospital controls.

Information on tea and dietary intakes, and possible confounders was collected using a structured questionnaire. The risk of prostate cancer for the intake of tea and lycopene and their joint effect were assessed using multivariate logistic regression models. Prostate cancer risk was reduced with increased consumption of green tea. The protective effect of green tea was significant (odds ratio 0.14, 95% CI: 0.06-0.35) for the highest quartile relative to the lowest after adjusting for total vegetables and fruits intakes and other potential confounding factors. Intakes of vegetables and fruits rich in lycopene were also inversely associated with prostate cancer risk (odds ratio 0.18, 95% CI 0.08-0.39). Interaction analysis showed that the protective effect from tea and lycopene consumption was synergistic (p<0.01).

This study suggests that habitual drinking tea and intakes of vegetables and fruits rich in lycopene could lead to a reduced risk of prostate cancer in Chinese men. Together they have a stronger preventive effect than either component taken separately. This is the first epidemiological study to investigate the joint effect between tea drinking and lycopene intake.

Polyphenols from green tea and pomegranate for prevention of prostate cancer.

Adhami VM, Mukhtar H. Free Radic Res. 2006 Oct;40(10):1095-104.
Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA.

Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in North America with similar trends in many Western countries. Geographic, epidemiological and laboratory studies suggest a role for dietary constituents in the etiology as well as prevention of PCa. The rising incidence of PCa in several countries appears to be coincidental with adoption of western lifestyle. Increase in the incidence of PCa has also been found in Asian populations migrating to the west. These facts give numerous leads to explore testable PCa prevention strategies. There is growing evidence in support of use of dietary ingredients in prevention and treatment of PCa. While substantial data exists in favor of use of polyphenols from tea as PCa chemopreventive agent, interest in anti-cancer properties of polyphenols from pomegranate has recently emerged. This review summarizes current literature on the effects of polyphenols from green tea and pomegranate against PCa.

Green tea polyphenols as a natural tumour cell proteasome inhibitor.

Dou QP, Landis-Piwowar KR, Chen D, Huo C, Wan SB, Chan TH. Inflammopharmacology. 2008 Sep 26. The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Rd, Detroit, Michigan, 48201, USA, doup@karmanos.org.

The cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG] are widely supported by results from epidemiological, cell culture, animal and clinical studies although the molecular target has not been well defined. We previously reported that ester bond-containing tea polyphenols, e. g. (-)-EGCG, and their synthetic analogs potently and specifically inhibited the proteasomal activity. Subsequently, we further demonstrated that methylation on green tea polyphenols under physiological conditions decreased their proteasome-inhibitory activity, contributing to decreased cancer-preventive effects of tea consumption. Since (-)-EGCG is unstable under physiological conditions, we also developed the peracetate-protected or prodrug form of (-)-EGCG, Pro-EGCG (1), and shown that Pro-EGCG (1) increases the bioavailability, stability, and proteasome-inhibitory and anticancer activities of (-)-EGCG in human breast cancer cells and xenografts, suggesting its potential use for cancer prevention and treatment.

Antinociceptive effect of resveratrol in carrageenan-evoked hyperalgesia in rats: Prolonged effect related to COX-2 expression impairment.

Pham-Marcou TA, Beloeil H, Sun X, Gentili M, Yaici D, Benoit G, Benhamou D, Mazoit JX.
Universite Paris-Sud, Laboratoire d'Anesthésie, EA 3540, Faculté de Médecine, 63 rue Gabriel Peri, F-94276 Le Kremlin Bicêtre, France. Pain. 2008 Sep 22.

Resveratrol is a natural polyphenol that protects from cancer and cardiovascular diseases. Resveratrol is able to induce apoptotic cell death and it inhibits the cyclooxygenase (COX) cascade. We measured the antinociceptive effect of resveratrol on carrageenan-induced hyperalgesia, prostaglandin-E2 (PGE2) concentration in CSF and COX-1/COX-2 gene expression in the spinal cord and dorsal root ganglion (DRG) in rats. Resveratrol induced a prolonged antinociceptive effect, which was correlated to the inhibition of COX-2 mRNA increase in DRG and cord elicited by carrageenan.

An increase in the basal threshold of mechanical nociception was also observed with resveratrol in the absence of any inflammatory insult. A rapid bilateralisation of COX-2 mRNA production, not accompanied by a parallel increase in c-Fos expression, was observed in spinal cord three hours after the inflammatory insult. This increase in COX-2 mRNA concentration in the spinal cord on the opposite side of the inflammatory insult was abolished by resveratrol. In conclusion, the antinociceptive effect exhibited by resveratrol was related to the prevention of COX-2 mRNA increase induced by carrageenan. Resveratrol also prevented the bilateralisation of COX-2 expression. The later effect, together with the prolonged analgesia induced by a single injection, may be of great benefit for preventing chronic pain states often seen after inflammatory insults.

Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells.

Hsieh TC, Wu JM. Int J Oncol. 2008 Oct;33(4):851-9.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.

Numerous dietary phytochemicals have shown anti-breast carcinogenic activities when tested in vitro; however, in most cases, the demonstrated efficacy of individual phytochemicals requires doses not readily achievable in vivo. Therefore, whether diets might exert translational promises and benefits in clinical settings and prevention of breast cancer remain unclear. Since cancer cells are endowed with complex, redundant, converging and diverging pathways spanning both the genetic and metabolic networks that are not merely replicates of those in normal cells, it is of interest to test whether a multicomponent approach involving lower, physiologically relevant doses of natural dietary agents may be developed as a chemopreventive strategy for breast cancer.

Herein, we investigated, using the estrogen receptor-positive MCF-7 breast cancer cells as a model, whether the combination of epigallocatechin gallate (EGCG), resveratrol and gamma-tocotrienol at suboptimal doses elicits synergism in suppressing cell proliferation, modulating gene expression, and increasing antioxidant activity, as compared to each of the three phytochemicals added alone. The results showed that there was a approximately 33, 50 and 58% inhibition of cell proliferation by > or =50 microM EGCG, > or =25 microM resveratrol and > or =10 microM gamma-tocotrienol, respectively, added as a single agent. When a suboptimal dose (10 microM) of each phytochemical was used, a significant additive effect in suppression of cell proliferation was observed with the combination of resveratrol and gamma-tocotrienol whereas the three phytochemicals added together did not produce more pronounced inhibition of cell proliferation.

A significant additive effect in reducing cyclin D1 and bcl-2 expression was found when gamma-tocotrienol was added with either EGCG or resveratrol. Functional synergism among the three phytochemicals was only observed in the induction of quinone reductase NQO1. These results suggest that diet-based protection against breast cancer may partly derive from synergy amongst dietary phytochemicals directed against specific molecular targets in responsive breast cancer cells, and provide support for the feasibility of the development of a diet-based combinatorial approach in the prevention and treatment of breast cancer.

Anti cancer effects of curcumin: cycle of life and death.

Sa G, Das T. Cell Div. 2008 Oct 3;3:14. India. gauri@bic.boseinst.ernet.in.
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata, 700054,

ABSTRACT: Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53.

In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.