DOI QR코드

DOI QR Code

Role of Pentacyclic Triterpenoids in Chemoprevention and Anticancer Treatment: An Overview on Targets and Underling Mechanisms

  • Ghante, Mahavir H. (Centre for Research in Pharmaceutical Sciences, Sharda Bhavan Education Society's Nanded Pharmacy College) ;
  • Jamkhande, Prasad G. (Centre for Research in Pharmaceutical Sciences, Sharda Bhavan Education Society's Nanded Pharmacy College)
  • Received : 2018.11.17
  • Accepted : 2019.03.20
  • Published : 2019.06.28

Abstract

The incidences of cancer are continuously increasing worldwide, affecting life of millions of people. Several factors associated with the internal and external environment are responsible for this deadly disease. The key internal determinants like abnormal hormonal regulation, genetic mutations and external determinants such as lifestyle and occupational factors enhances onset of cancer. From the ancient time, plants were remained as the most trusted source of medicine for the treatment of diverse disease conditions. Extensive studies have been performed for the discovery of effective anticancer agent from the plant and still it is going on. Pentacyclic triterpenoids are biologically active phytochemicals having a different range of activities such as anti-inflammatory, hepatoprotective, anti-hypertensive, antiulcerogenic and anti-tumor. These compounds generally contain ursane, oleanane, lupane and friedelane as a chief skeleton of pentacyclic triterpenoids which are generally present in higher plants. Isoprene unit, phytochemical, with good antitumor/anticancer activity is required for the biosynthesis of pentacyclic triterpenoids. Mechanisms such as cytotoxicity, DNA polymerase inhibition, regulation of apoptosis, change in signal transductions, interfere with angiogenesis and dedifferentiation, antiproliferative activity and metastasis inhibition are might be responsible for their anticancer effect. Present review spotlights diverse targets, mechanisms and pathways of pentacyclic triterpenoids responsible for anticancer effect.

Keywords

cancer;pentacyclic triterpenoids;apoptosis;anti-angiogenic;isoprene;antiproliferative

DHOCBS_2019_v22n2_55_f0001.png 이미지

Figure 1 Altered gene expression associated cancer development.

DHOCBS_2019_v22n2_55_f0001.png 이미지

Figure 1 Altered gene expression associated cancer development.

DHOCBS_2019_v22n2_55_f0002.png 이미지

Figure 3 Principal pathways such as angiogenesis, metastasis, proliferation and growth factors as targets for the treatment of cancer.

DHOCBS_2019_v22n2_55_f0002.png 이미지

Figure 3 Principal pathways such as angiogenesis, metastasis, proliferation and growth factors as targets for the treatment of cancer.

DHOCBS_2019_v22n2_55_f0003.png 이미지

Figure 4 Extrinsic Pathway (Death receptor pathway) is activated when a tumor necrosis factor (TNF) receptor is stimulated by particular death ligands that recruits proteins (adaptor protein) and activate initiator caspases (caspases 8) which further activate effector caspases (caspase 3). Whereas, intrinsic pathway (mitochondrial pathway) activate other signals, such as being DNA damage which cannot be repaired, the p53 (tumor suppressor gene) protein activates a subpathway that leads to release of cytochrome c from the mitochondrion, with successive participation of the apoptosome [a complex of procaspase 9, cytochrome c and apoptic activating protease factor-1 (Apaf-1)], and activation of caspasen 3 (initiator caspases) and caspase 9. R→ Receptor for growth factors, trophic factor and cell to cell contact factor (Continuous stimulation to this receptor is necessary for cell survival). Fas ligand→Trans membrane receptor that induce apoptosis. miRNAs→ micro RNAs that negatively regulate gene expression. p53→ tumor suppressor protein.

DHOCBS_2019_v22n2_55_f0003.png 이미지

Figure 4 Extrinsic Pathway (Death receptor pathway) is activated when a tumor necrosis factor (TNF) receptor is stimulated by particular death ligands that recruits proteins (adaptor protein) and activate initiator caspases (caspases 8) which further activate effector caspases (caspase 3). Whereas, intrinsic pathway (mitochondrial pathway) activate other signals, such as being DNA damage which cannot be repaired, the p53 (tumor suppressor gene) protein activates a subpathway that leads to release of cytochrome c from the mitochondrion, with successive participation of the apoptosome [a complex of procaspase 9, cytochrome c and apoptic activating protease factor-1 (Apaf-1)], and activation of caspasen 3 (initiator caspases) and caspase 9. R→ Receptor for growth factors, trophic factor and cell to cell contact factor (Continuous stimulation to this receptor is necessary for cell survival). Fas ligand→Trans membrane receptor that induce apoptosis. miRNAs→ micro RNAs that negatively regulate gene expression. p53→ tumor suppressor protein.

Table 1 Major class f pentacyclic triterpenoid, their st ucture and examples.

DHOCBS_2019_v22n2_55_t0001.png 이미지

Table 1 Major class f pentacyclic triterpenoid, their st ucture and examples.

DHOCBS_2019_v22n2_55_t0001.png 이미지

Table 2 Pentacyclic triterpenoids with anticancer activity and their mechanisms.

DHOCBS_2019_v22n2_55_t0002.png 이미지

Table 2 Pentacyclic triterpenoids with anticancer activity and their mechanisms.

DHOCBS_2019_v22n2_55_t0002.png 이미지

Figure 2 Chemical structure of squalene.

DHOCBS_2019_v22n2_55_t0003.png 이미지

Figure 2 Chemical structure of squalene.

DHOCBS_2019_v22n2_55_t0003.png 이미지

References

  1. Loney T, Aw TC, Handysides DG Ali R, Blair I, Grivna M, Shah SM, et al. An analysis of the health status of the United Arab Emirates: the 'Big 4'public health issues. Global health action. 2013;6:1-8.
  2. Dhanamani M, Devi SL, Kannan S. Ethnomedicinal plants for cancer therapy - a review. Hygeia JD Med. 2011;3:1-10.
  3. Singh MP, Kumar V, Agarwal A, Kumar R, Bhatt ML, Misra S. Clinico-epidemiological study of oral squamous cell carcinoma: A tertiary care centre study in North India. J Oral Biol Craniofac Res. 2016;6:32-35. https://doi.org/10.1016/j.jobcr.2015.11.002
  4. Rang HP, Ritter JM, Flower RJ. Rang and Dale's Pharmacology: With student consult online access: Elsevier Health Sciences. 7th edition. Churchill Livingstone: Edinburgh; 2012.
  5. Wang FZ, Yang NN, Zhao YL, Liu QQ, Fei HR, Zhang JG. PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells. Toxicol Lett. 2013;220:150-156. https://doi.org/10.1016/j.toxlet.2013.04.018
  6. Niedzwiecki A, Roomi MW, Kalinovsky T, Rath M. Anticancer Efficacy of Polyphenols and Their Combinations. Nutrients. 2016;8:552. https://doi.org/10.3390/nu8090552
  7. Safarzadeh E, ShotorbaniSS, Baradaran B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv Pharm Bull. 2014;4:421-427.
  8. Fabio GD, Romanucci V, De Marco A, Zarrelli A. Triterpenoids from Gymnema sylvestre and their pharmacological activities. Molecules. 2014;19:10956-10981.
  9. Pratheeshkumar P, Sreekala C, Zhang Z, Budhraja A, Ding S, Son YO, Wang X, Hitron A, Hyun-Jung K, Wang L, Lee JC. Cancer prevention with promising natural products: mechanisms of action and molecular targets. Anticancer Agents Med Chem. 2012;12:1159-1184. https://doi.org/10.2174/187152012803833035
  10. Shu L, Cheung KL, Khor TO, Chen C, Kong AN. Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev. 2010;29:483-502. https://doi.org/10.1007/s10555-010-9239-y
  11. Muffler K, Leipold D, Scheller MC, Haas C, Steingroewer J, Bley T, Neuhaus HE, Mirata MA, Schrader J, Ulber R. Biotransformation of triterpenes. Process Biochemistry. 2011;46:1-15. https://doi.org/10.1016/j.procbio.2010.07.015
  12. Martinez A, Rivas F, Perojil A, Parra A, Garcia-Granados A, Fernandez-Vivas A. Biotransformation of oleanolic and maslinic acids by Rhizomucor miehei. Phytochemistry. 2013;94:229-237. https://doi.org/10.1016/j.phytochem.2013.05.011
  13. Parmar S, Sharma T, Airao V, Bhatt R, Aghara R, Chavda S, Rabadiya SO, Gangwal AP. Neuropharmacological effects of triterpenoids. Phytopharmacology. 2013;4:354-372.
  14. Pollier J, Goossens A. Oleanolic acid. Phytochemistry. 2012;77:10-15. https://doi.org/10.1016/j.phytochem.2011.12.022
  15. Maia JL, Lima-Junior RC, Melo CM, David JP, David JM, Campos AR, Santos FA, Rao VS. Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: possible mechanisms. Pharmacol Res. 2006;54:282-286. https://doi.org/10.1016/j.phrs.2006.06.003
  16. Moreira DLF, de-Souza GHB, Rodrigues IV, Lopes NP, de Oliveira AR. A non-michaelian behavior of the in vitro metabolism of the pentacyclic triterpene alfa and beta amyrins by employing rat liver microsomes. J Pharm Biomed Anal. 2013;84:14-19. https://doi.org/10.1016/j.jpba.2013.05.038
  17. Csuk R, Siewert B, Dressel C, Schafer R. Tormentic acid derivatives: synthesis and apoptic activity. Eur J Med Chem. 2012;56:237-245. https://doi.org/10.1016/j.ejmech.2012.08.032
  18. Mandal A, Ghosh S, Bothra AK, Nanda AK, Ghosh P. Synthesis of friedelan triterpenoid analogs with DNA topoisomerase $II{\alpha}$ inhibitory activity and their molecular docking studies. Eur J Med Chem. 2012;54:137-143.
  19. American Cancer Society, Cancer Facts & Figures 2016, Atlanta: American Cancer Society; 2016.
  20. International Agency for Research on Cancer and Cancer Research UK. World Cancer Factsheet, Cancer Research UK, London; 2012.
  21. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.
  22. Ali I, Wani WA, Saleem K. Cancer scenario in India with future perspectives. Cancer Ther. 2011;8:56-70.
  23. Pittayapan P. Health Insurance for Cancer Care in Asia: Thailand. Asia Pac J Oncol Nurs. 2016;3:54. https://doi.org/10.4103/2347-5625.178173
  24. Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J Womens Health. 2015;7:405-414.
  25. Dsouza ND, Murthy N, Aras R. Projection of cancer incident cases for India-till 2026. Asian Pac J Cancer Prev. 2013;14:4379-4386. https://doi.org/10.7314/APJCP.2013.14.7.4379
  26. Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, et al. Cancer mortality in India: a nationally representative survey. The Lancet. 2012;379:1807-1816. https://doi.org/10.1016/S0140-6736(12)60358-4
  27. James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules. 2009;14:3922-3941. https://doi.org/10.3390/molecules14103922
  28. Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta med. 2009;75:1549-1560. https://doi.org/10.1055/s-0029-1186102
  29. Reyes CP, Nunez MJ, Jimenez IA, Busserolles J, Alcaraz MJ, Bazzocchi IL. Activity of lupane triterpenoids from Maytenus species as inhibitors of nitric oxide and prostaglandin E 2. Bioorg Med Chem. 2006;14:1573-1579. https://doi.org/10.1016/j.bmc.2005.10.063
  30. Yan XJ, Gong LH, Zheng FY, Cheng KJ, Chen ZS, Shi Z. Triterpenoids as reversal agents for anticancer drug resistance treatment. Drug Discov Today. 2014;19:482-488. https://doi.org/10.1016/j.drudis.2013.07.018
  31. Yan J, Sun L, Zhang X, Li Z, Zhou L, Qiu M. Serratene Triterpenoids from Palhinhaea cernua var. sikkimensis. Chem Pharm Bull (Tokyo). 2009;57:1381-1384.
  32. Wittayalai S, Sathalalai S, Thorroad S, Worawittayanon P, Ruchirawat S, Thasana N. Lycophlegmariols A-D: Cytotoxic serratene triterpenoids from the club moss Lycopodium phlegmaria L. Phytochemistry. 2012;76:117-123. https://doi.org/10.1016/j.phytochem.2012.01.006
  33. Feng JH, Chen W, Zhao Y, Ju XL. Anti-tumor activity of oleanolic, ursolic and glycyrrhetinic acid. The Open Natural Products Journal. 2009;2:48-52. https://doi.org/10.2174/1874848100902010048
  34. Soldi C, Pizzolatti MG, Luiz AP, Marcon R, Meotti FC, Mioto LA, et al. Synthetic derivatives of the $\alpha$-and $\beta$-amyrin triterpenes and their antinociceptive properties. Bioorg Med Chem. 2008;16:3377-3386. https://doi.org/10.1016/j.bmc.2007.12.008
  35. Kvasnica M, Sarek J, Klinotova E, Dzubak P, Hajduch M. Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. Bioorg Med Chem. 2005;13:3447-3454. https://doi.org/10.1016/j.bmc.2005.03.006
  36. Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A. Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents. Bioorg Med Chem. 2006;14:6713-6725. https://doi.org/10.1016/j.bmc.2006.05.075
  37. Patocka J. Biologically active pentacyclic triterpenes and their current medicine signification. J Appl Biomed. 2003;1:7-12. https://doi.org/10.32725/jab.2003.002
  38. Bishayee A, Ahmed S, Brankov N, Perloff M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci. 2011;16:980. https://doi.org/10.2741/3730
  39. Li ZJ, Yao C, Liu SF, Chen L, Xi YM, Zhang W, et al. Cytotoxic effect of icaritin and its mechanisms in inducing apoptosis in human burkitt lymphoma cell line. Biomed Res Int. 2014;1-7.
  40. Andreeff M, Goodrich DW, Pardee AB. Cell proliferation, differentiation, and apoptosis. In: Kufe DW, Pollock RE, Weichselbaum RR editors. Holland-Frei Cancer Medicine. 6th edit. Hamilton (ON): BC Decker;2003.
  41. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205-214.
  42. Wang SR, Fang WS. Pentacyclic triterpenoids and their saponins with apoptosis-inducing activity. Curr Top Med Chem. 2009;9:1581-1596. https://doi.org/10.2174/156802609789909821
  43. Janakiram NB, Indranie C, Malisetty SV, Jagan P, Steele VE, Rao CV. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344 rats and modulation of COX-2 and apoptosis in human colon HT-29 cancer cells. Pharm Res. 2008;25:2151-2157. https://doi.org/10.1007/s11095-008-9582-7
  44. Kanda T, Yokosuka O. The androgen receptor as an emerging target in hepatocellular carcinoma. J Hepatocell Carcinoma. 2015;2:91-99.
  45. Fritz WA, Lin TM, Peterson RE. The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. Carcinogenesis. 2008;29:1077-1082. https://doi.org/10.1093/carcin/bgn069
  46. Senese S, Lo Y, Huang D, Zangle TA, Gholkar AA, Robert L, et al. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. Cell Death Dis. 2014;5:e1462. https://doi.org/10.1038/cddis.2014.420
  47. Lu JJ, Dang YY, Huang M, Xu WS, Chen XP, Wang YT. Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae-A review. J Ethnopharmacol. 2012;143: 406-411. https://doi.org/10.1016/j.jep.2012.07.009
  48. Kim SS, Won SJ, Kim NJ, Cho SD, Choi HS. 3-Oxoolean-12-en-27-oic acid isolated from Aceriphyllum rossii induces caspase-8-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull. 2009;32:91-98. https://doi.org/10.1248/bpb.32.91
  49. Youn SH, Lee JS, Lee MS, Cha EY, Thuong PT, Kim JR, Chang ES. Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells. Biol Pharm Bull. 2012;35:105-110. https://doi.org/10.1248/bpb.35.105
  50. Sun CC, Zhang YS, Xue X, Cheng YN, Liu HP, Zhao CR, et al. Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma. Eur J Pharmacol. 2011;667:136-143. https://doi.org/10.1016/j.ejphar.2011.06.013
  51. Harsh M. Textbook of pathology. Jaypee Brothers Medical Publishers. New Delhi; 2010.
  52. Hu Y, Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res. 2012;2:340-356.
  53. Ebner F, Schremmer-Danninger E, Rehbock J. The role of TP53 and p21 gene polymorphisms in breast cancer biology in a well specified and characterized German cohort. J Cancer Res Clin Oncol. 2010;136:1369-1375. https://doi.org/10.1007/s00432-010-0788-9
  54. Mutai C, Abatis D, Vagias C, Moreau D, Roussakis C, Roussis V. Cytotoxic lupane-type triterpenoids from Acacia mellifera. Phytochemistry. 2004;65:1159-1164.
  55. Ketron AC, Osheroff N. Phytochemicals as anticancer and chemopreventive topoisomerase II poisons. Phytochem Rev. 2013;13:19-35.
  56. Sun H, Fang WS, Wang WZ, Hu C. Structure-activity relationships of oleanane-and ursane-type triterpenoids. Botanical Studies. 2006;47:339-368.
  57. Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: factors inducing DNA damage and virus integration. Cancers. 2014;6: 2155-2186. https://doi.org/10.3390/cancers6042155
  58. Nath R, RoyS, De B, Choudhury MD. Anticancer and antioxidant activity of croton: a review. Int J Pharm Pharm Sci. 2013;5:63-70.
  59. Ramachandran S, Prasad NR. Effect of ursolic acid, a triterpenoid antioxidant, on ultraviolet-B radiation-induced cytotoxicity, lipid peroxidation and DNA damage in human lymphocytes. Chem Biol Interact. 2008;176:99-107. https://doi.org/10.1016/j.cbi.2008.08.010
  60. Furtado RA, Rodrigues EP, Araujo FR, Oliveira WL, Furtado MA, Castro MB, et al. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1, 2-dimethylhydrazine in rat colon. Toxicol Pathol. 2008;36:576-580. https://doi.org/10.1177/0192623308317423
  61. Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Ursolic acid in cancer prevention and treatment:molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol. 2013;85:1579-1587. https://doi.org/10.1016/j.bcp.2013.03.006
  62. Lopez-Hortas L, Perez-Larran P, Gonzalez-Munoz MJ, Falque E, Dominguez H. Recent developments on the extraction and application of ursolic acid. A review. Food Research International. 2018;103:130-149. https://doi.org/10.1016/j.foodres.2017.10.028
  63. Kangsamaksin T, Chaithongyot S, Wootthichairangsan C, Hanchaina R, Tangshewinsirikul C, Svasti J. Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-$\alpha$. Plos One. 2017;12:1-16.
  64. Turan I, Demir S, Kilinc K, Yaman SO, Misir S, Kara H, et al. Cytotoxic effect of Rosa canina extract on human colon cancer cells through repression of telomerase expression. Journal of Pharmaceutical Analysis. 2018;8(6):394-399. https://doi.org/10.1016/j.jpha.2017.12.005
  65. Thoppil RJ, Bishayee A. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World J Hepatol. 2011;3:228-249. https://doi.org/10.4254/wjh.v3.i9.228
  66. Salminen A, Lehtonen M, Suuronen T, Kaarniranta K, Huuskonen J. Terpenoids: natural inhibitors of NF-${\kappa}B$ signaling with anti-inflammatory and anticancer potential. Cell Mol Life Sci. 2008;65:2979-2999. https://doi.org/10.1007/s00018-008-8103-5
  67. Satomi Y, Nishino H, Shibata S. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. Anticancer Res. 2005; 25:4043-4047.
  68. Grace-Lynn C, Darah I, Chen Y, Latha LY, Jothy SL, Sasidharan S. In vitro antioxidant activity potential of lantadene A, a pentacyclic triterpenoid of Lantana plants. Molecules. 2012;17:11185-11198. https://doi.org/10.3390/molecules170911185
  69. Patel S. A weed with multiple utility: Lantana camara. Reviews in Environmental Science and Bio/Technology. 2011;10:341-351. https://doi.org/10.1007/s11157-011-9254-7
  70. Kaur J, Sharma M, Sharma P, Bansal MP. Antitumor activity of lantadenes in DMBA/TPA induced skin Tumors in mice: expression of transcription factors. Am J Biomed Sci. 2010;2:79-90.
  71. Sharma M, Sharma P, Bansal M, Singh J. Lantadene A-induced apoptosis in human leukemia HL-60 cells. Indian J Pharmacol. 2007;39:140. https://doi.org/10.4103/0253-7613.33433
  72. Wynendaele W, OosteromVA, Pawinski A, De Bruijn EA, Maesi RA. Angiogenesis: possibilities for therapeutic interventions. Pharm World Sci. 1998;20:225-235. https://doi.org/10.1023/A:1008600603059
  73. Prasad S, Kalra N, Shukla Y. Induction of apoptosis by lupeol and mango extract in mouse prostate and LNCaP cells. Nutr Cancer. 2008;60:120-130.
  74. Juan ME, Planas JM, Ruiz-Gutierrez V, Daniel H, Wenzel U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br J Nutr. 2008;100:36-43. https://doi.org/10.1017/S0007114508882979
  75. Mu X, Shi W, Sun L, Li H, Li H, Jiang Z, et al. Pristimerin, a triterpenoid, inhibits tumor angiogenesis by targeting VEGFR2 activation. Molecules. 2012;17:6854-6868. https://doi.org/10.3390/molecules17066854
  76. Swain SS, Rout KK, Chand PK. Production of triterpenoid anti-cancer compound taraxerol in Agrobacterium-transformed root cultures of butterfly pea (Clitoria ternatea L.). Appl Biochem Biotechnol. 2012;168:487-503.
  77. Khanal P, Oh WK, Thuong PT, Cho SD, Choi HS. 24-Hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase. Planta Med. 2010;76:689-693. https://doi.org/10.1055/s-0029-1240678
  78. Neto CC. Ursolic acid and other pentacyclic triterpenoids: anticancer activities and occurrence in berries. Berries and Cancer Prevention. Springer New York; 2011.