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Phytosterols for Cancer Treatment Powerpoint

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Josh Nooner

Phytosterols show promise for cancer treatment based on several animal, in vitro, and human studies. Animal studies found that phytosterol supplementation delayed breast cancer tumor onset and reduced prostate cancer growth. In vitro studies demonstrated that phytosterols increased cancer cell apoptosis, decreased proliferation, and increased tumor suppressor genes. A human epidemiological study associated higher phytosterol intake with a 50% reduced risk of lung cancer. Collectively, the studies suggest phytosterols may exert anticancer effects through reducing oxidative damage, inhibiting growth and metastasis, and altering gene expression. However, more research is still needed, including long-term human clinical trials.

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Phytosterols for Cancer Treatment Josh Nooner, BS, CSCS Phytochemicals 11/19/15
Objectives Provide a brief overview of phytosterols List food sources and bioavailability Examine dosing and contraindications Provide a literature review of human, animal, and in vitro studies Discuss major research findings and applicability to human health and disease
Introduction Phytosterols - Plant-derived compounds that are similar in structure and function to cholesterol Includes both sterols and stanols o Sterols - Have a double bond in the sterol ring (90%) o Stanols Lack a double bond in the sterol ring (10%) The most abundant sterols in plants and the human diet are sitosterol and campesterol Shown to reduce LDL cholesterol, improve lipid profiles, and prevent cardiovascular disease But what are the effects on cancer?
Food Sources Food Source Amount of Beta- Sitosterol in 3.5oz portion Amount of Beta- Sitosterol in 200 calories Avocado 260mg 95 mg Vegetable oil 240mg 93mg Margarine 215mg 77mg Pistachios 200mg 71mg Hazelnuts 90mg 34mg Dark Chocolate 90mg 34mg Macadamias 85mg 30mg Pecans 75mg 27mg Walnuts 57mg 20mg 1 Egg 42mg 15mg o Avocados o Vegetable oils o Fortified margarine o Nuts o Seeds o Dark Chocolate
Bioavailability Studies show a range of absorption from 0.5-8% Very low bioavailability, caused by 3 mechanisms o Low absorption into the enterocyte o Poor esterification once inside the enterocyte o High biliary excretion rate once in the liver
Major Research Findings Most anticancer effects of phytosterols have been demonstrated in animal and in vitro studies Need to be confirmed in carefully controlled human clinical trials Epidemiological studies - Only studies that have been done in humans I will review 8 research articles o 4 animal studies o 3 in vitro studies o 1 human epidemiological study
Animal Studies
Animal Study 1: Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer Methods: 4-week-old female PyMT Tg mice were randomized into 2 groups. Those consuming and those not consuming a 2% phytosterol supplement added to the powdered food on either an 1. LFLC diet (6.2% fat, no cholesterol, energy density 3.1 kcal/g, calories from protein, fat and carbohydrate, 24%, 18% and 58%, respectively 2. HFHC diet (21.2% fat, 0.2% cholesterol, energy density 4.5 kcal/g, calories from protein, fat and carbohydrate, 15.2%, 42% and 42.7%, respectively o Phytosterols were composed of 20% campesterol, 22% stigmasterol and 41% 硫- sitosterol o Mice were maintained on the diets until euthanized (at 4, 8 or 13 weeks of age)
Animal Study 1: Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer Dietary phytosterol supplementation delayed tumor onset and progression in the setting of a typical Western diet The protection against cancer provided by phytosterols occurred at the same dose that reduced blood cholesterol and cardiovascular risk Phytosterols decreased levels of Cyclin D1, a gene that leads to breast cancer when activated
Animal Study 2: In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells Methods: PC-3 cells: supplemented with either cholesterol, campesterol, or beta-sitosterol. o Tested tumor invasiveness, cell migration, In vivo: Mice were fed for two weeks ad libitum either 1. Cholesterol supplemented diet 2. Phytosterol supplemented diet o Tumor cells were then injected and their growth was monitored for 8 weeks
Animal Study 2: In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells Results: Cell density and cell migration were significantly reduced in the phytosterol supplemented cells Total tumor area at 8 wks was significantly lower in the phytosterol fed mice
Animal Study 3: Protective effect of plant sterols against chemically induced colon tumors in rats Methods: 4 experimental groups 1. Control chow and intracolonic0.9% NaCIsolution N=10 2. Control chow plus B-sitosterol (0.2%) and intracolonic 0.9% NaCI solution N=10 3. Control chow and intracolonic MNU3 N=71 4. Control chow plus B-sitosterol (0.2%) and intracolonic MNU N=48 28 week intervention period At Week 28, the colon was opened, and the number of tumors was recorded
Animal Study 3: Protective effect of plant sterols against chemically induced colon tumors in rats Results: Decrease in colonic tumor formation when the plant sterol B-sitosterol was added to the diet
Animal Study 4: 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫- sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen- responsive breast cancer cells in vitro and in ovariectomized athymic mice Methods: Estrogen pellet and MCF-7 cells injected into ovariectomized female mice. 4 experimental groups: 1. Negative control 2. BSS (Beta Sitosterol) 3. BSSG (Beta Sitosterol glucoside) 4. MC (BSS:BSSG = 99:1) Estrogenic and antiestrogenic effects of dietary phytosterols on tumor growth measured 18 week intervention period
Animal Study 4: 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫- sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen- responsive breast cancer cells in vitro and in ovariectomized athymic mice Results: Dietary BSS and MC reduced E2-induced MCF-7 tumor growth Dietary phytosterols lowered the plasma E2 level by 35.3%
In Vitro Studies
In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Methods: o 硫-sitosterol was isolated from A. curassavica leaves. o The ability to induce apoptosis was determined by its in vitro antiradical activity and cytotoxic studies using human colon adenocarcinoma cell lines. 1,2-dimethylhydrazine (DMH, 20 mg/kg b.w.) was injected into male Wistar rats. Rats were supplemented with 硫-sitosterol in 3 different concentrations 1. 5 mg/kg bw 2. 10 mg/kg bw 3. 20 mg/kg bw 16 week experimental period
In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Significant induction of apoptotic cells by B-sitosterol
In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Significant reduction in ACF lesions with increased B-sitosterol Dose dependent decrease in B-Catenin (cell adhesion) and PCNA (DNA Replication) genes
In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene Methods: PC-3 and DU145 cells were treated with either cholesterol or phytosterols for 72h o Necrosis and cell growth were measured o Induction of cell growth-suppressor gene expression was evaluated o Apoptosis was evaluated
In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene NDRG1 gene (tumor suppressor gene) increased with campsiterol Caveolin 1 gene (tumor suppressor gene) increased with campsiterol
In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene Decrease in anti-apoptotic genes and increase in pro-apoptotic and tumor suppressor genes in phytosterol group Opposite effect in cholesterol group
In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Methods: SGC-7901 human stomach cancer cells Proliferation, cytotoxicity, and apoptosis were examined using various assays and western blotting Cells treated with different concentrations of 硫-sitosterol
In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Dose dependent decrease in proliferation of stomach cancer cells
In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Results: B-sitosterol increases expression of pro-apoptotic genes, decreases anti-apoptotic genes B-sitosterol decreases size of stomach cancer cells
Human Studies
Human Study 1: Phytosterols and risk of lung cancer: a case-control study in Uruguay Methods: All patients with newly diagnosed primary lung cancer diagnosed in the four major hospitals of Montevideo included. 463 cases with lung cancer and 465 hospitalized controls Detailed medical, lifestyle, and diet questionnaire 96% response rate
Human Study 1: Phytosterols and risk of lung cancer: a case-control study in Uruguay Significantly lower risk of developing lung cancer in the highest quintiles of phytosterol consumption
Mechanisms
Dosing Studies recommend 200-400mg/day of phytosterols o This will keep the serum level at the necessary concentration to see positive effects o Must keep the serum concentration relatively constant o Eat a variety of phytosterol containing foods daily Most Americans get 80mg/day
Contraindications Two cases where people should avoid phytosterols 1. Those with Sitosterolemia A very rare hereditary disease that results from a mutation in both copies of the ABCG5 or ABCG8 gene o Rare autosomal recessive inherited lipid metabolic disorder o ABC transport proteins ineffective o Leads to elevated blood sterols, atherosclerosis, and xanthomas 2. Those pregnant and lactating Lack of research in this area
Application to Human Health and Disease Phytosterols shown to: 1. Increase apoptosis of cancerous cells 2. Reduce ROS levels and prevent oxidative damage 3. Increase antioxidant enzymes 4. Reduce blood cholesterol 5. Decrease inflammatory cytokines 6. Decrease angiogenesis Phytosterols are a promising treatment for many types of cancer Will be used as a dietary intervention in a clinical setting in the future
Future Studies Short and long term effects Interactions with prescription drugs Mechanisms of prevention
Research Summary Research Article Area Investigated Results Llaverias, G., Escol-Gil, J. C., Lerma, E., Julve, J., Pons, C., Cabr辿, A., ... & Blanco-Vaca, F. (2013). Examined the effects of a dietary phytosterol supplement on tumor onset and progression in breast cancer. Dietary phytosterol supplementation delayed tumor onset and progression in the setting of a typical Western diet and suggest that phytosterols may exert these anticancer effects by preventing oxidative damage. Awad, A. B., Fink, C. S., Williams, H., & Kim, U The dietary effect of phytosterols vs. cholesterol on the growth and metastasis of the PC-3 human prostate cancer cells in SCID mice. Phytosterols both indirectly and directly inhibited the growth and metastasis of PC-3 cells. Raicht, R. F., Cohen, B. I., Fazzini, E. P., Sarwal, A. N., & Takahashi, M The effect of B-sitosterol on colon tumor formation in rats treated with a carcinogen. There is a decrease in colonic tumor formation when the plant sterol B-sitosterol was added to the diet. Ju, Y. H., Clausen, L. M., Allred, K. F., Almada, A. L., & Helferich, W. G. Evaluated the estrogenic and antiestrogenic effects of BSS, BSSG, and MC (0.001 to 150 mol/L) on the proliferation of Michigan Cancer Foundation 7 (MCF-7) cells in vitro. BSS and MC stimulated MCF-7 cell growth in vitro. Although BSSG comprises only 1% of MC, BSSG made MC less estrogenic than BSS alone in vitro. However, dietary BSS and MC protected against E2-stimulated MCF-7 tumor growth and lowered circulating E2 levels. Baskar, A. A., Ignacimuthu, S., Paulraj, G. M., & Al Numair, K. S. To broaden the understanding of the anticancer potential of 硫-sitosterol in in vitro cancer model and DMH-induced experimental colon carcinogenesis model. 硫-sitosterol induced significant dose-dependent growth inhibition of colon cells, induced apoptosis by scavenging reactive oxygen species, and suppressed the expression of 硫-catenin and PCNA antigens in human colon cancer cells. Ifere, G. O., Equan, A., Gordon, K., Nagappan, P., Igietseme, J. U., & Ananaba, G. A To show the distinction between the apoptotic and anti- proliferative signaling of phytosterols and cholesterol- enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N-myc downstream-regulated gene 1 (NDRG1), a pro-apoptotic androgen-regulated tumor suppressor. Cholesterol-enrichment promoted cell growth (P<0.05), while phytosterols significantly induced growth- suppression (P<0.05) and apoptosis. Cell cycle analysis showed that contrary to cholesterol, phytosterols decreased mitotic subpopulations Zhao, Y., Chang, S. K., Qu, G., Li, T., & Cui, H. Investigate the effect of 硫-sitosterol on proliferation and apoptosis in SGC-7901 stomach cancer cells in vitro and to study the possible mechanisms of action involved. B-sitosterol suppresses the proliferation and induces the cell cytotoxicity of SGC-7901 stomach cancer cells in a time and dose-dependent manner. Mendilaharsu, M., De Stefani, E., Deneo-Pellegrini, H., Carzoglio, J., & Ronco, A. To establish a possible protective role of plant sterols in lung carcinogenesis. Total plant sterol intake was associated with a reduction in risk of 50% when contrasting the upper exposure quartile with the lower.
References Awad, A. B., Fink, C. S., Williams, H., & Kim, U. (2001). In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. European Journal of Cancer Prevention, 10(6), 507-513. Baskar, A. A., Ignacimuthu, S., Paulraj, G. M., & Al Numair, K. S. (2010). Chemopreventive potential of 硫- sitosterol in experimental colon cancer model-an in vitro and in vivo study. BMC complementary and alternative medicine,10(1), 24. Bradford, P. G., & Awad, A. B. (2007). Phytosterols as anticancer compounds.Molecular nutrition & food research, 51(2), 161-170. Bradford, P. G., & Awad, A. B. (2010). Modulation of signal transduction in cancer cells by phytosterols. Biofactors, 36(4), 241-247. Ding, H., Chin, Y. W., Kinghorn, A. D., & DAmbrosio, S. M. (2007, October). Chemopreventive characteristics of avocado fruit. In Seminars in cancer biology (Vol. 17, No. 5, pp. 386-394). Academic Press. Higdon, J. (2005). Phytosterols. Retrieved from http://lpi.oregonstate.edu/mic/dietary- factors/phytochemicals/phytosterols Ifere, G. O., Equan, A., Gordon, K., Nagappan, P., Igietseme, J. U., & Ananaba, G. A. (2010). Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene. Cancer epidemiology, 34(4), 461-471. Ju, Y. H., Clausen, L. M., Allred, K. F., Almada, A. L., & Helferich, W. G. (2004). 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫-sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in ovariectomized athymic mice. The journal of nutrition,134(5), 1145-1151.
References Cont. Landauer, E. (2008). Healthy Male Prostate Diet. Retrieved from http://www.peak-health-now.com/male-prostate- diet.html Llaverias, G., Escol-Gil, J. C., Lerma, E., Julve, J., Pons, C., Cabr辿, A., ... & Blanco-Vaca, F. (2013). Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer. The Journal of nutritional biochemistry, 24(1), 39-48. Mendilaharsu, M., De Stefani, E., Deneo-Pellegrini, H., Carzoglio, J., & Ronco, A. (1998). Phytosterols and risk of lung cancer: a case-control study in Uruguay. Lung Cancer, 21(1), 37-45. Raicht, R. F., Cohen, B. I., Fazzini, E. P., Sarwal, A. N., & Takahashi, M. (1980). Protective effect of plant sterols against chemically induced colon tumors in rats. Cancer Research, 40(2), 403-405. Ramprasath, V. R., & Awad, A. B. (2015). Role of Phytosterols in Cancer Prevention and Treatment. Journal of AOAC International. Woyengo, T. A., Ramprasath, V. R., & Jones, P. J. H. (2009). Anticancer effects of phytosterols. European Journal of Clinical Nutrition, 63(7), 813-820. Zhao, Y., Chang, S. K., Qu, G., Li, T., & Cui, H. (2009). 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC- 7901 human stomach cancer cells.Journal of agricultural and food chemistry, 57(12), 5211-5218.
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Phytosterols for Cancer Treatment Powerpoint

  • 1. Phytosterols for Cancer Treatment Josh Nooner, BS, CSCS Phytochemicals 11/19/15
  • 2. Objectives Provide a brief overview of phytosterols List food sources and bioavailability Examine dosing and contraindications Provide a literature review of human, animal, and in vitro studies Discuss major research findings and applicability to human health and disease
  • 3. Introduction Phytosterols - Plant-derived compounds that are similar in structure and function to cholesterol Includes both sterols and stanols o Sterols - Have a double bond in the sterol ring (90%) o Stanols Lack a double bond in the sterol ring (10%) The most abundant sterols in plants and the human diet are sitosterol and campesterol Shown to reduce LDL cholesterol, improve lipid profiles, and prevent cardiovascular disease But what are the effects on cancer?
  • 4. Food Sources Food Source Amount of Beta- Sitosterol in 3.5oz portion Amount of Beta- Sitosterol in 200 calories Avocado 260mg 95 mg Vegetable oil 240mg 93mg Margarine 215mg 77mg Pistachios 200mg 71mg Hazelnuts 90mg 34mg Dark Chocolate 90mg 34mg Macadamias 85mg 30mg Pecans 75mg 27mg Walnuts 57mg 20mg 1 Egg 42mg 15mg o Avocados o Vegetable oils o Fortified margarine o Nuts o Seeds o Dark Chocolate
  • 5. Bioavailability Studies show a range of absorption from 0.5-8% Very low bioavailability, caused by 3 mechanisms o Low absorption into the enterocyte o Poor esterification once inside the enterocyte o High biliary excretion rate once in the liver
  • 6. Major Research Findings Most anticancer effects of phytosterols have been demonstrated in animal and in vitro studies Need to be confirmed in carefully controlled human clinical trials Epidemiological studies - Only studies that have been done in humans I will review 8 research articles o 4 animal studies o 3 in vitro studies o 1 human epidemiological study
  • 8. Animal Study 1: Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer Methods: 4-week-old female PyMT Tg mice were randomized into 2 groups. Those consuming and those not consuming a 2% phytosterol supplement added to the powdered food on either an 1. LFLC diet (6.2% fat, no cholesterol, energy density 3.1 kcal/g, calories from protein, fat and carbohydrate, 24%, 18% and 58%, respectively 2. HFHC diet (21.2% fat, 0.2% cholesterol, energy density 4.5 kcal/g, calories from protein, fat and carbohydrate, 15.2%, 42% and 42.7%, respectively o Phytosterols were composed of 20% campesterol, 22% stigmasterol and 41% 硫- sitosterol o Mice were maintained on the diets until euthanized (at 4, 8 or 13 weeks of age)
  • 9. Animal Study 1: Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer Dietary phytosterol supplementation delayed tumor onset and progression in the setting of a typical Western diet The protection against cancer provided by phytosterols occurred at the same dose that reduced blood cholesterol and cardiovascular risk Phytosterols decreased levels of Cyclin D1, a gene that leads to breast cancer when activated
  • 10. Animal Study 2: In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells Methods: PC-3 cells: supplemented with either cholesterol, campesterol, or beta-sitosterol. o Tested tumor invasiveness, cell migration, In vivo: Mice were fed for two weeks ad libitum either 1. Cholesterol supplemented diet 2. Phytosterol supplemented diet o Tumor cells were then injected and their growth was monitored for 8 weeks
  • 11. Animal Study 2: In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells Results: Cell density and cell migration were significantly reduced in the phytosterol supplemented cells Total tumor area at 8 wks was significantly lower in the phytosterol fed mice
  • 12. Animal Study 3: Protective effect of plant sterols against chemically induced colon tumors in rats Methods: 4 experimental groups 1. Control chow and intracolonic0.9% NaCIsolution N=10 2. Control chow plus B-sitosterol (0.2%) and intracolonic 0.9% NaCI solution N=10 3. Control chow and intracolonic MNU3 N=71 4. Control chow plus B-sitosterol (0.2%) and intracolonic MNU N=48 28 week intervention period At Week 28, the colon was opened, and the number of tumors was recorded
  • 13. Animal Study 3: Protective effect of plant sterols against chemically induced colon tumors in rats Results: Decrease in colonic tumor formation when the plant sterol B-sitosterol was added to the diet
  • 14. Animal Study 4: 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫- sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen- responsive breast cancer cells in vitro and in ovariectomized athymic mice Methods: Estrogen pellet and MCF-7 cells injected into ovariectomized female mice. 4 experimental groups: 1. Negative control 2. BSS (Beta Sitosterol) 3. BSSG (Beta Sitosterol glucoside) 4. MC (BSS:BSSG = 99:1) Estrogenic and antiestrogenic effects of dietary phytosterols on tumor growth measured 18 week intervention period
  • 15. Animal Study 4: 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫- sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen- responsive breast cancer cells in vitro and in ovariectomized athymic mice Results: Dietary BSS and MC reduced E2-induced MCF-7 tumor growth Dietary phytosterols lowered the plasma E2 level by 35.3%
  • 17. In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Methods: o 硫-sitosterol was isolated from A. curassavica leaves. o The ability to induce apoptosis was determined by its in vitro antiradical activity and cytotoxic studies using human colon adenocarcinoma cell lines. 1,2-dimethylhydrazine (DMH, 20 mg/kg b.w.) was injected into male Wistar rats. Rats were supplemented with 硫-sitosterol in 3 different concentrations 1. 5 mg/kg bw 2. 10 mg/kg bw 3. 20 mg/kg bw 16 week experimental period
  • 18. In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Significant induction of apoptotic cells by B-sitosterol
  • 19. In Vitro Study 1: Chemopreventive potential of 硫-sitosterol in experimental colon cancer model-an in vitro and in vivo study Significant reduction in ACF lesions with increased B-sitosterol Dose dependent decrease in B-Catenin (cell adhesion) and PCNA (DNA Replication) genes
  • 20. In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene Methods: PC-3 and DU145 cells were treated with either cholesterol or phytosterols for 72h o Necrosis and cell growth were measured o Induction of cell growth-suppressor gene expression was evaluated o Apoptosis was evaluated
  • 21. In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene NDRG1 gene (tumor suppressor gene) increased with campsiterol Caveolin 1 gene (tumor suppressor gene) increased with campsiterol
  • 22. In Vitro Study 2: Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene Decrease in anti-apoptotic genes and increase in pro-apoptotic and tumor suppressor genes in phytosterol group Opposite effect in cholesterol group
  • 23. In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Methods: SGC-7901 human stomach cancer cells Proliferation, cytotoxicity, and apoptosis were examined using various assays and western blotting Cells treated with different concentrations of 硫-sitosterol
  • 24. In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Dose dependent decrease in proliferation of stomach cancer cells
  • 25. In Vitro Study 3: 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells Results: B-sitosterol increases expression of pro-apoptotic genes, decreases anti-apoptotic genes B-sitosterol decreases size of stomach cancer cells
  • 27. Human Study 1: Phytosterols and risk of lung cancer: a case-control study in Uruguay Methods: All patients with newly diagnosed primary lung cancer diagnosed in the four major hospitals of Montevideo included. 463 cases with lung cancer and 465 hospitalized controls Detailed medical, lifestyle, and diet questionnaire 96% response rate
  • 28. Human Study 1: Phytosterols and risk of lung cancer: a case-control study in Uruguay Significantly lower risk of developing lung cancer in the highest quintiles of phytosterol consumption
  • 30. Dosing Studies recommend 200-400mg/day of phytosterols o This will keep the serum level at the necessary concentration to see positive effects o Must keep the serum concentration relatively constant o Eat a variety of phytosterol containing foods daily Most Americans get 80mg/day
  • 31. Contraindications Two cases where people should avoid phytosterols 1. Those with Sitosterolemia A very rare hereditary disease that results from a mutation in both copies of the ABCG5 or ABCG8 gene o Rare autosomal recessive inherited lipid metabolic disorder o ABC transport proteins ineffective o Leads to elevated blood sterols, atherosclerosis, and xanthomas 2. Those pregnant and lactating Lack of research in this area
  • 32. Application to Human Health and Disease Phytosterols shown to: 1. Increase apoptosis of cancerous cells 2. Reduce ROS levels and prevent oxidative damage 3. Increase antioxidant enzymes 4. Reduce blood cholesterol 5. Decrease inflammatory cytokines 6. Decrease angiogenesis Phytosterols are a promising treatment for many types of cancer Will be used as a dietary intervention in a clinical setting in the future
  • 33. Future Studies Short and long term effects Interactions with prescription drugs Mechanisms of prevention
  • 34. Research Summary Research Article Area Investigated Results Llaverias, G., Escol-Gil, J. C., Lerma, E., Julve, J., Pons, C., Cabr辿, A., ... & Blanco-Vaca, F. (2013). Examined the effects of a dietary phytosterol supplement on tumor onset and progression in breast cancer. Dietary phytosterol supplementation delayed tumor onset and progression in the setting of a typical Western diet and suggest that phytosterols may exert these anticancer effects by preventing oxidative damage. Awad, A. B., Fink, C. S., Williams, H., & Kim, U The dietary effect of phytosterols vs. cholesterol on the growth and metastasis of the PC-3 human prostate cancer cells in SCID mice. Phytosterols both indirectly and directly inhibited the growth and metastasis of PC-3 cells. Raicht, R. F., Cohen, B. I., Fazzini, E. P., Sarwal, A. N., & Takahashi, M The effect of B-sitosterol on colon tumor formation in rats treated with a carcinogen. There is a decrease in colonic tumor formation when the plant sterol B-sitosterol was added to the diet. Ju, Y. H., Clausen, L. M., Allred, K. F., Almada, A. L., & Helferich, W. G. Evaluated the estrogenic and antiestrogenic effects of BSS, BSSG, and MC (0.001 to 150 mol/L) on the proliferation of Michigan Cancer Foundation 7 (MCF-7) cells in vitro. BSS and MC stimulated MCF-7 cell growth in vitro. Although BSSG comprises only 1% of MC, BSSG made MC less estrogenic than BSS alone in vitro. However, dietary BSS and MC protected against E2-stimulated MCF-7 tumor growth and lowered circulating E2 levels. Baskar, A. A., Ignacimuthu, S., Paulraj, G. M., & Al Numair, K. S. To broaden the understanding of the anticancer potential of 硫-sitosterol in in vitro cancer model and DMH-induced experimental colon carcinogenesis model. 硫-sitosterol induced significant dose-dependent growth inhibition of colon cells, induced apoptosis by scavenging reactive oxygen species, and suppressed the expression of 硫-catenin and PCNA antigens in human colon cancer cells. Ifere, G. O., Equan, A., Gordon, K., Nagappan, P., Igietseme, J. U., & Ananaba, G. A To show the distinction between the apoptotic and anti- proliferative signaling of phytosterols and cholesterol- enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N-myc downstream-regulated gene 1 (NDRG1), a pro-apoptotic androgen-regulated tumor suppressor. Cholesterol-enrichment promoted cell growth (P<0.05), while phytosterols significantly induced growth- suppression (P<0.05) and apoptosis. Cell cycle analysis showed that contrary to cholesterol, phytosterols decreased mitotic subpopulations Zhao, Y., Chang, S. K., Qu, G., Li, T., & Cui, H. Investigate the effect of 硫-sitosterol on proliferation and apoptosis in SGC-7901 stomach cancer cells in vitro and to study the possible mechanisms of action involved. B-sitosterol suppresses the proliferation and induces the cell cytotoxicity of SGC-7901 stomach cancer cells in a time and dose-dependent manner. Mendilaharsu, M., De Stefani, E., Deneo-Pellegrini, H., Carzoglio, J., & Ronco, A. To establish a possible protective role of plant sterols in lung carcinogenesis. Total plant sterol intake was associated with a reduction in risk of 50% when contrasting the upper exposure quartile with the lower.
  • 35. References Awad, A. B., Fink, C. S., Williams, H., & Kim, U. (2001). In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. European Journal of Cancer Prevention, 10(6), 507-513. Baskar, A. A., Ignacimuthu, S., Paulraj, G. M., & Al Numair, K. S. (2010). Chemopreventive potential of 硫- sitosterol in experimental colon cancer model-an in vitro and in vivo study. BMC complementary and alternative medicine,10(1), 24. Bradford, P. G., & Awad, A. B. (2007). Phytosterols as anticancer compounds.Molecular nutrition & food research, 51(2), 161-170. Bradford, P. G., & Awad, A. B. (2010). Modulation of signal transduction in cancer cells by phytosterols. Biofactors, 36(4), 241-247. Ding, H., Chin, Y. W., Kinghorn, A. D., & DAmbrosio, S. M. (2007, October). Chemopreventive characteristics of avocado fruit. In Seminars in cancer biology (Vol. 17, No. 5, pp. 386-394). Academic Press. Higdon, J. (2005). Phytosterols. Retrieved from http://lpi.oregonstate.edu/mic/dietary- factors/phytochemicals/phytosterols Ifere, G. O., Equan, A., Gordon, K., Nagappan, P., Igietseme, J. U., & Ananaba, G. A. (2010). Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth- suppressor gene. Cancer epidemiology, 34(4), 461-471. Ju, Y. H., Clausen, L. M., Allred, K. F., Almada, A. L., & Helferich, W. G. (2004). 硫-sitosterol, 硫-sitosterol glucoside, and a mixture of 硫-sitosterol and 硫-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in ovariectomized athymic mice. The journal of nutrition,134(5), 1145-1151.
  • 36. References Cont. Landauer, E. (2008). Healthy Male Prostate Diet. Retrieved from http://www.peak-health-now.com/male-prostate- diet.html Llaverias, G., Escol-Gil, J. C., Lerma, E., Julve, J., Pons, C., Cabr辿, A., ... & Blanco-Vaca, F. (2013). Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer. The Journal of nutritional biochemistry, 24(1), 39-48. Mendilaharsu, M., De Stefani, E., Deneo-Pellegrini, H., Carzoglio, J., & Ronco, A. (1998). Phytosterols and risk of lung cancer: a case-control study in Uruguay. Lung Cancer, 21(1), 37-45. Raicht, R. F., Cohen, B. I., Fazzini, E. P., Sarwal, A. N., & Takahashi, M. (1980). Protective effect of plant sterols against chemically induced colon tumors in rats. Cancer Research, 40(2), 403-405. Ramprasath, V. R., & Awad, A. B. (2015). Role of Phytosterols in Cancer Prevention and Treatment. Journal of AOAC International. Woyengo, T. A., Ramprasath, V. R., & Jones, P. J. H. (2009). Anticancer effects of phytosterols. European Journal of Clinical Nutrition, 63(7), 813-820. Zhao, Y., Chang, S. K., Qu, G., Li, T., & Cui, H. (2009). 硫-Sitosterol inhibits cell growth and induces apoptosis in SGC- 7901 human stomach cancer cells.Journal of agricultural and food chemistry, 57(12), 5211-5218.