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Review Article

Beta-Sitosterol: A Promising but Orphan Nutraceutical to Fight Against Cancer

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Pages 1216-1222 | Received 22 Sep 2014, Accepted 23 Aug 2015, Published online: 16 Oct 2015

REFERENCES

  • Awad AB and Fink CS: Phytosterols as anticancer dietary components: evidence and mechanism of action. J Nutr 130, 2127–2130, 2000.
  • Vanhanen HT and Miettinen TA: Effects of unsaturated and saturated dietary plant sterols on their serum contents. Clin Chim Acta 205, 97–107, 1992.
  • Muti P, Awad AB, Schunemann H, Fink CS, Hovey K, et al.: A plant food-based diet modifies the serum β-sitosterol concentration in hyperandrogenic postmenopausal women. J Nutr 133, 4252–4255, 2003.
  • Bhattacharyya AK: Uptake and esterification of plant sterols by rat small intestine. Am J Physiol 240, G50–G55, 1981.
  • Duchateau G, Cochrane B, Windebank S, Herudzinska J, Sanghera D, et al.: Absolute oral bioavailability and metabolic turnover of β-sitosterol in healthy subjects. Drug Metab Dispos. 40, 2026–2030, 2012.
  • Salen G, Ahrens EH Jr, and Grundy SM: Metabolism of β-sitosterol in man. J Clin Invest 49, 952–967, 1970.
  • Aringer L and Eneroth P: Formation and metabolism in vitro of 5,6- epoxides of cholesterol and β-sitosterol. J Lipid Res 15, 389–398, 1974.
  • Aringer L, Eneroth P, and Nordstrom L: Side chain hydroxylation of cholesterol, campesterol and β-sitosterol in rat liver mitochondria. J Lipid Res 17, 263–272, 1976.
  • Awad AB, von Holtz RL, Cone JP, Fink CS, and Chen YC: Beta-Sitosterol inhibits growth of HT-29 human colon cancer cells by activating the sphingomyelin cycle. Anticancer Res 18, 471–473, 1998.
  • Awad AB, Williams H, and Fink CS: Phytosterols reduce in vitro metastatic ability of MDA-MB-231 human breast cancer cells. Nutr. Cancer 40, 157–164, 2001.
  • Awad AB, Burr AT, and Fink CS: Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells. Prostaglandins Leukot. Essent. Fatty Acids 72, 219–226, 2005.
  • Choi YH, Kong KR, Kim YA, Jung KO, Kil JH, et al.: Induction of Bax and activation of caspases during beta-sitosterol-mediated apoptosis in human colon cancer cells. Int J Oncol 23, 1657–1662, 2003.
  • Awad AB, Roy R, and Fink CS: Beta-sitosterol, a plant sterol, induces apoptosis and activates key caspases in MDA-MB-231 human breast cancer cells. Oncol. Rep 10, 497–500, 2003.
  • Awad AB, Chinnam M, Fink CS, and Bradford PG: β-sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine 14, 747–754, 2007.
  • Moon DO, Kyeong-Jun L, Yung HC, and Gi-Young K: β-Sitosterol-induced apoptosis is mediated by the activation of ERK and the downregulation of Akt in MCA-102 murine fibrosarcoma cells. Int Immunopharmacol 7, 1044–1053, 2007.
  • Jayaprakash GK, Mandadi KK, Poulose SM, Jadegoud Y, Nagana GGA, et al.: Inhibition of colon cancer cell growth and antioxidant activity of bioactive compounds from Poncirus trifoliata (L.) Raf. Bioorg Med Chem 14, 4923–4932, 2007.
  • Vivancos M and Moreno JJ: Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic Biol Med 39, 91–97, 2005.
  • Moon DO, Kim MO, Choi YH, and Kim GY: beta-Sitosterol induces G2/M arrest, endoreduplication, and apoptosis through the Bcl-2 and PI3K/Akt signaling pathways. Cancer Lett 264, 181–191, 2008.
  • Moreno JJ: Effect of olive oil minor components on oxidative stress and arachidonic acid mobilization and metabolism by macrophages RAW 264.7. Free Radic Biol Med 35, 1073–1081, 2003.
  • von Holtz RL, Fink CS, and Awad AB: Beta-sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr. Cancer 32, 8–12, 1998.
  • Hueber AO: Role of membrane microdomain rafts in TNFR-mediated signal transduction. Cell Death Differ 10, 7–9, 2003.
  • Scheel-Toellner D, Wang K, Assi LK, Webb PR, Craddock RM, et al.: Clustering of death receptors in lipid rafts initiates neutrophil spontaneous apoptosis. Biochem Soc Trans 32, 679–681, 2004.
  • Awad AB, Chinnam M, Fink CS, and Bradford PG: Targeting ceramide by dietary means to stimulate apoptosis in tumor cells. Curr Top Nutra Res 2, 93–100, 2004.
  • Ling WH and Jones PJH: Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci 57, 195–206, 1995.
  • Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, et al.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer, 2013. Available from: http://globocan.iarc.fr, accessed on 18/03/2014
  • Bray F, Ren JS, Masuyer E, and Ferlay J: Estimates of global cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132, 1133–1145, 2013. doi:10.1002/ijc.27711
  • Ames BN, Gold LS, and Willet WC: The causes and prevention of cancer. Proc Natl Acad Sci USA 92, 5258–5265, 1995.
  • Sieri S, Krogh V, Pala V, Muti P, Micheli A, et al.: Dietary patterns and risk of breast cancer in the ORDET cohort. Cancer Epidemiol Biomarkers Prev 13, 567–572, 2004.
  • Greenwald P, Clifford CK, and Milner JA: Diet and cancer prevention. Eur J Cancer 37, 948–965, 2001.
  • Pagliacci MC, Smacchia M, Migliorati G, Grignani F, Riccardi C, et al.: Growth-inhibitory effects of the natural phytooestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer 30, 1675–1682, 1994.
  • MacLatchy DL and Van Der Kraak GJ: The phytoestrogen beta-sitosterol alters the reproductive endocrine status of goldfish. Toxicol Appl Pharmacol 134, 305–312, 1995.
  • Clodi K, Wimmer D, Li Y, Goodwin R, Jaeger U, Mann G, et al.: Expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukemia cells. Br J Haematol 111, 580–586, 2000.
  • Fulda S, Jeremias I, and Debatin KM: Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 23, 7611–7620, 2004.
  • MacFarlane M, Harper N, Snowden RT, Dyer MJ, Barnett GA, et al.: Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukemia. Oncogene 21, 6809–6818, 2002.
  • Awad AB, Barta SL, Fink CS, and Bradford PG: Beta-Sitosterol enhances tamoxifen effectiveness on breast cancer cells by affecting ceramide metabolism. Mol Nutr Food Res 52, 419–426, 2008.
  • Bradford PG and Awad AB: Phytosterols: Bioactivity on cancer. In:, Nutrition and Cancer Prevention, Awad AB and Bradford PG (Eds.). Boca Raton, FL: Taylor and Francis, 2006, pp. 251–270.
  • Cabot MC, Giuliano AE, Volner A, and Han TY: Tamoxifen retards glycosphingolipid metabolism in human cancer cells. FEBS Lett 394, 129–131, 1996.
  • Perry A, Jenkins RB, O'Fallon JR, Schaefer PL, Kimmel DW, et al.: Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors: An analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Cancer 86, 672–683, 1999.
  • Ziliotto L, Barbisan L, and Rodrigues M: Lack of chemoprevention of dietary Agaricus blazei against rat colonic aberrant crypt foci. Hum Exp Toxicol 6, 505–511, 2008.
  • Inamine M, Suzui M, Morioka T, Kinjo T, Kaneshiro T, et al.: Inhibitory effect of dietary monoglucosylceramide1-O-betaglucosyl-N-2′-hydroxyarachidoyl-4,8-sphingadienine on two different categories of colon preneoplastic lesions induced by 1,2- dimethylhydrazine in F344 rats. Cancer Sci 12, 876–881, 2005.
  • Porter AC and Vaillancourt RR: Tyrosine kinase receptor-activated signal transduction pathway which lead to oncogenesis. Oncogene 17, 1343–1352, 1998.
  • Damalas A, Ben-Zeev A, Simcha I, Shtutman M, Leal JF, et al.: Excess beta-catenin promotes accumulation of transcriptionally active p53. EMBO J 18, 3054–3063, 1999.
  • Bravo R, Frank R, Blundell PA, and Macdonald-Bravo H: Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature 326, 515–517, 1987.
  • Toyokuni S, Okamoto K, Yodoi J, and Hiai H: Hypothesis: persistent oxidative stress in cancer. FEBS Lett 358, 1–3, 1995.
  • Baskar AA, Ignacimuthu S, Paulraj GM, and Al Numair KS: Chemopreventive potential of beta-Sitosterol in experimental colon cancer model-an in vitro and In vivo study. BMC Complement Altern Med 10, 24, 2010. doi:10.1186/1472-6882-10-24.
  • Baskar AA, Al Numair KS, Gabriel Paulraj M, Alsaif MA, Muamar MA, et al.: β-sitosterol prevents lipid peroxidation and improves antioxidant status and histoarchitecture in rats with 1,2-dimethylhydrazine-induced colon cancer. J Med Food 15, 335–343, 2012.
  • Shraibom N: Herbal combinations for treatment of a skin condition. In: Herbal Combinations for Treatment of a Skin Condition. US patent: US8597695, 2013.
  • Lu K, Lee MH, and Patel SB: Dietary cholesterol absorption; more than just bile. Trends Endocrinol Metab 12, 314–320, 2001.
  • Cruse P, Lewin M, and Clark CG: Dietary cholesterol is co-carcinogenic for human colon cancer. Lancet 1, 752–755, 1979.
  • Tseng TH, Hsu JD, Chu CY, and Wang CJ: Promotion of colon carcinogenesis through increasing lipid peroxidation induced in rats by a high cholesterol diet. Cancer Lett 100, 81–87, 1996.
  • Normén L, Dutta P, Lia A, and Andersson H: Soy sterol esters and beta-sitostanol ester as inhibitors of cholesterol absorption in human small bowel. Am J Clin Nutr 71, 908–913, 2000.
  • Heinemann T, Kullak-Ublick GA, Pietruck B, and von Bergmann K: Mechanisms of action of plant sterols on inhibition of cholesterol absorption. Comparison of sitosterol and sitostanol. Eur J Clin Pharmacol 40(Suppl 1), 59–63, 1991.
  • Ahn J, Sinha R, Pei Z, Dominianni C, Wu J, et al.: Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst 105, 1907–1911, 2013.
  • Mastromarino A, Reddy BS, and Wynder EL: Metabolic epidemiology of colon cancer: enzymic activity of fecal flora. Am J Clin Nutr 29, 1455–1460, 1976.
  • Reddy BS: Dietary fat and colon cancer: animal model studies. Lipids 27, 807–813, 1992.
  • Sengottuvelan M, Senthilkumar R, and Nalini N: Modulatory influence of dietary resveratrol during different phases of 1,2-dimethylhydrazine induced mucosal lipid-peroxidation, antioxidant status and aberrant crypt foci development in rat colon carcinogenesis. Biochim Biophys Acta 1760, 1175–1183, 2006.
  • Baskar AA, Al Numair KS, Al Saif M, Ignacimuthu S: Effect of dietary β-sitosterol on fecal bacterial and colonic biotransformation enzymes in 1,2-dimethylhydrazine–induced colon carcinogenesis. J Med Sci 42(Suppl. 1), 1307–1313, 2012.
  • Herbert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, et al.: Nutritional and socioeconomic factors in relation to prostate cancer. J Natl Cancer Inst 90, 1637–1647, 1998.
  • Weihrauch JL and Gardner JMZ: Sterol contents of foods of plant origin. J Am Diet Assoc 73, 39–47, 1978.
  • Awad AB, Chan KC, Downie AC, and Fink CS: Peanuts as a source of beta-sitosterol, a sterol with anticancer properties. Nutr Cancer 36, 238–241, 2000.
  • Homma Y, Gotoh M, Yokoyama O, Masumori N, Kawauchi A, et al.: Jua clinical guidelines for benign prostatic hyperplasia. International Journal of Urology 18, 741–756, 2011.
  • Berges RR, Kassen A, and Senge T: Treatment of symptomatic benign prostatic hyperplasia with beta-sitosterol: an 18-month follow-up. BJU Int 85, 842–846, 2000.
  • Wilt TJ, MacDonald R, and Ishani A: Beta-sitosterol for the treatment of benign prostatic hyperplasia: a systematic review. BJU Int 83, 976–983, 1999.
  • Duan RD: Anticancer compounds and sphingolipid metabolism in the colon. In Vivo 19, 293–300, 2005.
  • Awad AB, Fink CS, Williams H, Kim U: In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. Eur J Cancer Prev 10, 507–513, 2001.
  • von Holtz RL, Fink CS, and Awad AB: Beta-Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr Cancer 32, 8–12, 1998.
  • Awad, AB, von Holtz, RL, Cone, J, Fink, CS, and Chen, YC: Beta-Sitosterol inhibits the growth of HT-29 human colon cancer cells by activating the sphingomyelin cycle. Anticancer Res 18, 471–479, 1997.
  • Awad AB, Williams H, and Fink CS. Effect of phytosterols on cholesterol metabolism and MAP kinase in MDA-MB-231 human breast cancer cells. J Nutr Biochem 14, 111–119, 2003.
  • Cancer Research UK: Leukaemia. Accessed from http://publications.cancerresearchuk.org/cancerstats/stats_leukemia
  • Park C, Moon DO, Rhu CH, Choi BT, Lee WH, et al.: Beta-sitosterol induces anti-proliferation and apoptosis in human leukemic U937 cells through activation of caspase-3 and induction of Bax/Bcl-2 ratio. Biol Pharm Bull 30, 1317–1323, 2007.
  • Hinds MW, Kolonel LN, Lee J, and Hankin JH: Dietary cholesterol and lung cancer risk among men in Hawaii. Am J Clin Nutr 37, 192–193, 1983.
  • Goodman MT, Kolonel LN, Yoshizawa CN, and Hankin JH: The effect of dietary cholesterol and fat on the risk of lung cancer in Hawaii. Am J Epidemiol 128, 1241–1255, 1988.
  • Goodman MT, Hankin JH, Wilkens LR, and Kolonel LN: High-fat foods and the risk of lung cancer. Epidemiology 3, 288–299, 1992.
  • Jain M, Burch JD, Howe GR, Risch HA, and Miller AB: Dietary factors and risk of lung cancer: results from a case-control study, Toronto, 1981–1985. Int J Cancer 45, 287–293, 1990.
  • Knekt P, Seppanen R, Jarvinen R, Virtamo J, Hyvonen L, et al.: Dietary cholesterol, fatty acids, and the risk of lung cancer among men. Nutr Cancer 16, 267–275, 1991.
  • Shekelle RB, Rossof AH, and Stamler J: Dietary cholesterol and incidence of lung cancer: the Western Electric study. Am J Epidemiol 134, 480–484, 1991.
  • De Stefani E, Fontham ETH, Chen V, Correa P, Deneo-Pellegrini H, et al.: Fatty foods and the risk of lung cancer. A case-control study from Uruguay. Int J Cancer 71, 760–766, 1997.
  • De Stefani E, Deneo-Pellegrini H, Mendilaharsu M, Carzoglio JC, and Ronco A. Dietary fat and lung cancer: a case-control study in Uruguay. Cancer Causes Control 8, 913–921, 1997.
  • Ikeda I, Tanake K, Sugano M, Vagouny G, and Gallo L: Inhibition of cholesterol absortion in rats by plant sterols. J Lipid Res 29, 1573–1582, 1988.
  • Ikeda I, Tanake K, Sugano M, Vagouny G, and Gallo L: Discrimination between cholesterol and sitosterol for absortion in rats. J Lipid Res 29, 1583–1591, 1988.
  • Vundru SS, Kale RK, and Singh RP: β-Sitosterol induces G1 arrest and causes depolarization of mitochondrial membrane potential in breast carcinoma MDA-MB-231 cells. BMC Complement Altern Med 13, 280, 2013. doi:10.1186/1472-6882-13-280
  • McCann SE, Freudenheim JL, Marshall JR, and Graham S: Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nutr 133, 1937–1942, 2003.
  • Ling WH and Jones PJH: Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci 57, 195–206, 1995.
  • Jemal R, Siegel E, Ward T, Murray J, and Xu MJ: Cancer statistics, 2007. CA Cancer J. Clin 57, 43–66, 2007.
  • Valentini V and Cellini F: Radiotherapy in gastric cancer: a systematic review of literature and new perspectives, Expert Rev. Anticancer Ther 10, 1379–1393, 2007.
  • Zhao Y, Chang SK, Qu G, Li T, and Cui H: Beta-sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells. J Agric Food Chem 57, 5211–5218, 2009.
  • Ritschel WA, Kastner U, Hussain AS, and Koch HP: Pharmacokinetics and bioavailability of beta-sitosterol in the beagle dog. Arzneimittelforschung 40, 463–468, 1990.
  • Imanaka H, Koide H, Shimizu K, Asai T, Ishikado A, et al.: Chemoprevention of tumor metastasis by liposomal beta-sitosterol intake. Biol Pharm Bull 31, 400–404, 2008.
  • Borowy-Borowski H, Sodja C, Docherty J, Walker PR, and Sikorska M: Unique technology for solubilization and delivery of highly lipophilic bioactive molecules. J Drug Target 12, 415–424, 2004.
  • Sjöström B, Bergenståhl B, and Kronberg B: A method for the preparation of submicron particles of sparingly water-soluble drugs by precipitation in oil-in-water emulsions. II: Influence of the emulsifier, the solvent, and the drug substance. J Pharm Sci 82, 584–589, 1993.
  • Zhou Z, Li L, Yang Y, Xu X, and Huang Y: Tumor targeting by pH-sensitive, biodegradable, cross-linked N-(2-hydroxypropyl) methacrylamide copolymer micelles. Biomaterials 35, 6622–6635, 2014.
  • Lacatusu I, Badea N, Stan R, and Meghea A: Novel bio-active lipid nanocarriers for the stabilization and sustained release of sitosterol. Nanotechnology 23, 455702, 2012.
  • Farkas E, Schubert R, and Zelkó R: Effect of beta-sitosterol concentration and high pressure homogenization on the chlorhexidine release from vesicular gels. Int J Pharm 307, 51–55, 2006.
  • Upadhyay K, Gupta NK, and Dixit VK: Development and characterization of phyto-vesicles of β-sitosterol for the treatment of androgenetic alopecia. Arch Dermatol Res 304, 511–519, 2012.
  • Patel SP and Jarowski CI: Oral absorption efficiency of acid-labile antibiotics from lipid-drug delivery systems. J Pharm Sci 64, 869–872, 1975.
  • Joseph AA, Hill JL, Patel J, Patel S, and Kincl FA: Sustained-release hormonal preparations XV: release of progesterone from cholesterol pellets in vivo. J Pharm Sci 66, 490–493, 1977.
  • Maitani Y, Yano S, Hattori Y, Furuhata M, and Hayashi K: Liposome vector containing biosurfactant-complexed DNA as herpes simplex virus thymidine kinase gene delivery system. J Liposome Res 16, 359–372, 2006.
  • Zhang Y, Rong Qi X, Gao Y, Wei L, Maitani Y, et al.: Mechanisms of co-modified liver-targeting liposomes as gene delivery carriers based on cellular uptake and antigens inhibition effect. J Control Release 117, 281–290, 2007.
  • Hiruta Y, Hattori Y, Kawano K, Obata Y, and Maitani Y: Novel ultra-deformable vesicles entrapped with bleomycin and enhanced to penetrate rat skin. J Control Release 113, 146–154, 2006.
  • Maitani Y, Nakamura K, Suenaga H, Kamata K, Takayama K, et al.: The enhancing effect of soybean-derived sterylglucoside and beta-sitosterol beta-D-glucoside on nasal absorption in rabbits. Int J Pharm 200, 17–26, 2000.
  • Nakamura K, Takayama K, Nagai T, and Maitani Y: Regional intestinal absorption of FITC-dextran 4,400 with nanoparticles based on beta-sitosterol beta-D-glucoside in rats. J Pharm Sci 92, 311–318, 2003.
  • Elmowafy M, Viitala T, Ibrahim HM, Abu-Elyazid SK, Samy A, et al.: Silymarin loaded liposomes for hepatic targeting: in vitro evaluation and HepG2 drug uptake. Eur J Pharm Sci 50, 161–171, 2013.

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