Current Pharmacology Reports

, Volume 4, Issue 2, pp 157–169 | Cite as

The Mevalonate Pathway and Terpenes: a Diversity of Chemopreventatives

Cancer Chemoprevention (R Agarwal, K El Bayoumy and S Yu, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Cancer Chemoprevention


Purpose of Review

The goal of the present review is to give an overview of the most recent papers demonstrating the chemoprevention effects of terpenes. We were interested in showing the structural diversity of these compounds and elucidating overlapping mechanistic factors that may be responsible for chemoprevention by the terpenes in general in these effects.

Recent Findings

The studies reviewed point to chemoprevention effects across the broad array of structural classes of the terpenes, from the very small-molecule monoterpenes (10 carbon atoms) to the tetraterpenes (40 carbon atoms). These compounds have chemopreventative effects in cancers of the colon, bladder, skin, and liver. Some studies demonstrated that natural product mixtures have more robust effects and that synergy between compounds can be found in these natural products.


Terpenes are the most diverse class of compounds on earth. The complex biology of animals including the development of cancers has evolved with these compounds enabling numerous structurally diverse groups of the terpenes to have similar effects on the development and progression of cancers. Mechanistically, these actions tend to cluster into effects of reactive oxygen species and mediators of inflammation which are key players in carcinogenesis.


Mevalonate Isoprenoid Terpene Chemoprevention 


Compliance with Ethical Standards

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Christianson DW. Structural and chemical biology of terpenoid cyclases. Chem Rev. 2017;117(17):11570–648.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    •• Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75(3):311–35. Very good review of natural products as a source for therapeutics. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Holstein SA, Hohl RJ. Isoprenoids: remarkable diversity of form and function. Lipids. 2004;39(4):293–309.PubMedCrossRefGoogle Scholar
  4. 4.
    Liang PH, Ko TP, Wang AHJ. Structure, mechanism and function of prenyltransferases. Eur J Biochem. 2002;269(14):3339–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Thulasiram HV, Erickson HK, Poulter CD. Chimeras of two isoprenoid synthases catalyze all four coupling reactions in isoprenoid biosynthesis. Science. 2007;316(5821):73–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Thulasiram HV, Poulter CD. Farnesyl diphosphate synthase: the art of compromise between substrate selectivity and stereoselectivity. J Am Chem Soc. 2006;128(49):15819–23.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Hosfield DJ, Zhang Y, Dougan DR, Broun A, Tari LW, Swanson RV, et al. Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis. J Biol Chem. 2004;279(10):8526–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Burke CC, Wildung MR, Croteau R. Geranyl diphosphate synthase: cloning, expression, and characterization of this prenyltransferase as a heterodimer. Proc Natl Acad Sci U S A. 1999;96(23):13062–7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Holstein SA, Tong H, Kuder CH, Hohl RJ. Quantitative determination of geranyl diphosphate levels in cultured human cells. Lipids. 2009;44(11):1055–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Miziorko HM. Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys. 2011;505(2):131–43.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Rohmer M. The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat Prod Rep. 1999;16(5):565–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Rohmer M, Knani M, Simonin P, Sutter B, Sahm H. Isoprenoid biosynthesis in bacteria—a novel pathway for the early steps leading to isopentenyl diphosphate. Biochem J. 1993;295:517–24.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Koga Y, Morii H. Biosynthesis of ether-type polar lipids in archaea and evolutionary considerations. Microbiol Mol Biol Rev. 2007;71(1):97–120.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Lombard J, Moreira D. Origins and early evolution of the mevalonate pathway of isoprenoid biosynthesis in the three domains of life. Mol Biol Evol. 2011;28(1):87–99.PubMedCrossRefGoogle Scholar
  16. 16.
    Bohlmann J, Meyer-Gauen G, Croteau R. Plant terpenoid synthases: molecular biology and phylogenetic analysis. Proc Natl Acad Sci U S A. 1998;95(8):4126–33.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Chen F, Tholl D, Bohlmann J, Pichersky E. The family of terpene synthases in plants: a mid-size family of genes for specialized metabolism that is highly diversified throughout the kingdom. Plant J. 2011;66(1):212–29.PubMedCrossRefGoogle Scholar
  18. 18.
    Sacchettini JC, Poulter CD. Biochemistry—creating isoprenoid diversity. Science. 1997;277(5333):1788–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Poulter CD. Biosynthesis of non-head-to-tail terpenes—formation of 1′-1 and 1′-3 linkages. Acc Chem Res. 1990;23(3):70–7.CrossRefGoogle Scholar
  20. 20.
    Ourisson G, Albrecht P. Hopanoids 1. Geohapanoids—the most abundant natural-products on earth. Acc Chem Res. 1992;25(9):398–402.CrossRefGoogle Scholar
  21. 21.
    Ourisson G, Albrecht P, Rohmer M. Hopanoids—palaeochemistry and biochemistry of a group of natural products. Pure Appl Chem. 1979;51(4):709–29.CrossRefGoogle Scholar
  22. 22.
    Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem. 2007;40(9–10):575–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Burda P, Aebi M. The dolichol pathway of N-linked glycosylation. Biochimica Et Biophysica Acta-General Subjects. 1999;1426(2):239–57.CrossRefGoogle Scholar
  24. 24.
    Crane FL. Biochemical functions of coenzyme Q(10). J Am Coll Nutr. 2001;20(6):591–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Sagami H, Matsuoka S, Ogura K. Formation of Z,E,E-geranylgeranyl diphosphate by rat-liver microsomes. J Biol Chem. 1991;266(6):3458–63.PubMedGoogle Scholar
  26. 26.
    Sakaihara T, Honda A, Tateyama S, Sagami H. Subcellular fractionation of polyprenyl diphosphate synthase activities responsible for the syntheses of polyprenols and dolichols in spinach leaves. J Biochem. 2000;128(6):1073–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, et al. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2012;62(1):30–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Gilani AH, Atta ur R. Trends in ethnopharmacology. J Ethnopharmacol. 2005;100(1–2):43–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Kaur V, Kumar M, Kumar A, Kaur K, Dhillon VS, Kaur S. Pharmacotherapeutic potential of phytochemicals: implications in cancer chemoprevention and future perspectives. Biomed Pharmacother. 2018;97:564–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Surh YJ. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem Toxicol. 2002;40(8):1091–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Thomasset SC, Berry DP, Garcea G, Marczylo T, Steward WP, Gescher AJ. Dietary polyphenolic phytochemicals—promising cancer chemopreventive agents in humans? A review of their clinical properties. Int J Cancer. 2007;120(3):451–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Wu XW, Patterson S, Hawk E. Chemoprevention—history and general principles. Best Pract Res Clin Gastroenterol. 2011;25(4–5):445–59.PubMedCrossRefGoogle Scholar
  33. 33.
    Sporn MB. Approaches to prevention of epithelial cancer during preneoplastic period. Cancer Res. 1976;36(7):2699–702.PubMedGoogle Scholar
  34. 34.
    Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35(6):1332–8.PubMedGoogle Scholar
  35. 35.
    •• Adhami VM, Bailey HH, Mukhtar H. Cancer chemoprevention is not a failure. Carcinogenesis. 2014;35(9):2154–5. Part of a pair of papers of thought provoking papers on chemoprevention, with reference 36, this one is pro chemoprevention. PubMedCrossRefGoogle Scholar
  36. 36.
    •• Potter JD. The failure of cancer chemoprevention. Carcinogenesis. 2014;35(5):974–82. This is the other in the pair with reference 35, points out the failures and strikes an anti-chemoprevention stance. PubMedCrossRefGoogle Scholar
  37. 37.
    Gould MN. Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect. 1997;105:977–9.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    St Clair D, et al. Modulation of skin tumorigenesis by SOD. Biomed Pharmacother. 2005;59(4):209–14.PubMedCrossRefGoogle Scholar
  39. 39.
    Raju J. Azoxymethane-induced rat aberrant crypt foci: relevance in studying chemoprevention of colon cancer. World J Gastroenterol. 2008;14(43):6632–5.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Barnard DR, Xue RD. Laboratory evaluation of mosquito repellents against Aedes albopictus, Culex nigripalpus, and Ochlerotatus triseriatus (Diptera: Culicidae). J Med Entomol. 2004;41(4):726–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Girod SC, Pape HD, Krueger GRF. P53 and PCNA expression in carcinogenesis of the oropharyngeal mucosa. Oral Oncol Eur J Cancer Part B. 1994;30B(6):419–23.CrossRefGoogle Scholar
  42. 42.
    Jorge RM, Leite JPV, Oliveira AB, Tagliati CA. Evaluation of antinociceptive, anti-inflammatory and antiulcerogenic activities of Maytenus ilicifolia. J Ethnopharmacol. 2004;94(1):93–100.PubMedCrossRefGoogle Scholar
  43. 43.
    Bukhari SNA, Jantan I, Seyed MA. Effects of plants and isolates of Celastraceae family on cancer pathways. Anti Cancer Agents Med Chem. 2015;15(6):681–93.CrossRefGoogle Scholar
  44. 44.
    • Nunez MJ, et al. Dihydro-beta-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: structure-activity relationship. Eur J Med Chem. 2016;111:95–102. Primary reference for chemoprentative compound reviewed PubMedCrossRefGoogle Scholar
  45. 45.
    Prasad S, Kalra N, Shukla Y. Hepatoprotective effects of lupeol and mango pulp extract of carcinogen induced alteration in Swiss albino mice. Mol Nutr Food Res. 2007;51(3):352–9.PubMedCrossRefGoogle Scholar
  46. 46.
    He ZM, et al. Tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine as the basis for urothelial carcinogenesis. Mutat Res Genet Toxicol Environ Mutagen. 2012;742(1–2):92–5.CrossRefGoogle Scholar
  47. 47.
    Lee PS, et al. Chemoprevention by resveratrol and pterostilbene: targeting on epigenetic regulation. Biofactors. 2017;Google Scholar
  48. 48.
    Pashkow FJ, Watumull DG, Campbell CL. Astaxanthin: a novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am J Cardiol. 2008;101(10A):58D–68D.PubMedCrossRefGoogle Scholar
  49. 49.
    Crowell PL, Gould MN. Chemoprevention and therapy of cancer by d-limonene. Crit Rev Oncog. 1994;5(1):1–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Crowell PL, Kennan WS, Haag JD, Ahmad S, Vedejs E, Gould MN. Chemoprevention of mammary carcinogenesis by hydroxylated derivatives of d-limonene. Carcinogenesis. 1992;13(7):1261–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Elson CE, Yu SG. The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J Nutr. 1994;124(5):607–14.PubMedCrossRefGoogle Scholar
  52. 52.
    Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr. 1999;129(3):775S–8S.PubMedCrossRefGoogle Scholar
  53. 53.
    Farco JA, Grundmann O. Menthol—pharmacology of an important naturally medicinal “cool”. Mini-Rev Med Chem. 2013;13(1):124–31.PubMedCrossRefGoogle Scholar
  54. 54.
    Wang YZ, et al. Menthol inhibits the proliferation and motility of prostate cancer DU145 cells. Pathol Oncol Res. 2012;18(4):903–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Li Q, Wang X, Yang Z, Wang B, Li S. Menthol induces cell death via the TRPM8 channel in the human bladder cancer cell line T24. Oncology. 2009;77(6):335–41.PubMedCrossRefGoogle Scholar
  56. 56.
    • Liu ZG, et al. Chemopreventive efficacy of menthol on carcinogen-induced cutaneous carcinoma through inhibition of inflammation and oxidative stress in mice. Food Chem Toxicol. 2015;82:12–8. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  57. 57.
    Slaga TJ, Fischer SM, Nelson K, Gleason GL. Studies on the mechanism of skin tumor promotion—evidence for several stages in promotion. Proc Nat Acad Sci U S A–Biol Sci. 1980;77(6):3659–63.CrossRefGoogle Scholar
  58. 58.
    Slaga TJ, Fischer SM, Weeks CE, Klein-Szanto AJP, Reiners J. Studies on the mechanisms involved in multistage carcinogenesis in mouse skin. J Cell Biochem. 1982;18(1):99–119.PubMedCrossRefGoogle Scholar
  59. 59.
    Ma GZ, et al. Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation. Inflammation. 2013;36(2):457–67.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim SH, Kim MO, Gao P, Youm CA, Park HR, Lee SR, et al. Overexpression of extracellular superoxide dismutase (EC-SOD) in mouse skin plays a protective role in DMBA/TPA-induced tumor formation. Oncol Res. 2005;15(7–8):333–41.PubMedCrossRefGoogle Scholar
  61. 61.
    Khan AQ, Khan R, Rehman MU, Lateef A, Tahir M, Ali F, et al. Soy isoflavones (daidzein & genistein) inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cutaneous inflammation via modulation of COX-2 and NF-kappa B in Swiss albino mice. Toxicology. 2012;302(2–3):266–74.PubMedCrossRefGoogle Scholar
  62. 62.
    Vendramini-Costa DB, Carvalho JE. Molecular link mechanisms between inflammation and cancer. Curr Pharm Des. 2012;18(26):3831–52.PubMedCrossRefGoogle Scholar
  63. 63.
    Khan AQ, Khan R, Qamar W, Lateef A, Rehman MU, Tahir M, et al. Geraniol attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in mouse skin: possible role of p38 MAP kinase and NF-kappa B. Exp Mol Pathol. 2013;94(3):419–29.PubMedCrossRefGoogle Scholar
  64. 64.
    Kim JH, Kim MS, Bak Y, Chung IM, Yoon DY. The cadin-2-en-1 beta-ol-1 beta-D-glucuronopyranoside suppresses TPA-mediated matrix metalloproteinase-9 expression through the ERK signaling pathway in MCF-7 human breast adenocarcinoma cells. J Pharmacol Sci. 2012;118(2):198–205.PubMedCrossRefGoogle Scholar
  65. 65.
    • Sivaranjani A, Sivagami G, Nalini N. Chemopreventive effect of carvacrol on 1,2-dimethylhydrazine induced experimental colon carcinogenesis. J Cancer Res Ther. 2016;12(2):755–62. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  66. 66.
    Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen—preliminary findings. Cancer Lett. 1987;37(2):147–51.PubMedCrossRefGoogle Scholar
  67. 67.
    Bird RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett. 1995;93(1):55–71.PubMedCrossRefGoogle Scholar
  68. 68.
    McLellan EA, Bird RP. Aberrant crypts—potential preneoplastic lesions in the murine colon. Cancer Res. 1988;48(21):6187–92.PubMedGoogle Scholar
  69. 69.
    Arunasree KM. Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine. 2010;17(8–9):581–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Luo Y, Wu JY, Lu MH, Shi Z, Na N, di JM. Carvacrol alleviates prostate cancer cell proliferation, migration, and invasion through regulation of PI3K/Akt and MAPK signaling pathways. Oxidative Med Cell Longev. 2016;2016:1–11.Google Scholar
  71. 71.
    Patel, B., V.R. Shah, and S.A. Bavadekar, Anti-proliferative effects of carvacrol on human prostate cancer cell line, LNCaP. FASEB J, 2012. 26.Google Scholar
  72. 72.
    Jayakumar S, Madankumar A, Asokkumar S, Raghunandhakumar S, Gokula dhas K, Kamaraj S, et al. Potential preventive effect of carvacrol against diethylnitrosamine-induced hepatocellular carcinoma in rats. Mol Cell Biochem. 2012;360(1–2):51–60.PubMedCrossRefGoogle Scholar
  73. 73.
    • Chen JP, et al. Natural borneol enhances bisdemethoxycurcumin-induced cell cycle arrest in the G2/M phase through up-regulation of intracellular ROS in HepG2 cells. Food Funct. 2015a;6(3):740–8. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  74. 74.
    Li YB, Gao JL, Zhong ZF, Hoi PM, Ming-Yuen Lee S, Wang YT. Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways. Pharmacol Rep. 2013;65(3):700–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Anuchapreeda S, Tima S, Duangrat C, Limtrakul P. Effect of pure curcumin, demethoxycurcumin, and bisdemethoxycurcumin on WT1 gene expression in leukemic cell lines. Cancer Chemother Pharmacol. 2008;62(4):585–94.PubMedCrossRefGoogle Scholar
  76. 76.
    Yodkeeree S, Chaiwangyen W, Garbisa S, Limtrakul P. Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. J Nutr Biochem. 2009;20(2):87–95.PubMedCrossRefGoogle Scholar
  77. 77.
    Qi HP, Gao XC, Zhang LQ, Wei SQ, Bi S, Yang ZC, et al. In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Eur J Pharmacol. 2013;705(1–3):20–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Ru G, Han L, Qing J, Sheng J, Li R, Qiu M, et al. Effects of borneol on the pharmacokinetics of 9-nitrocamptothecin encapsulated in PLGA nanoparticles with different size via oral administration. Drug Deliv. 2016;23(9):3417–23.PubMedCrossRefGoogle Scholar
  79. 79.
    Su JY, et al. Preparation of natural borneol/2-hydroxypropyl-beta-cyclodextrin inclusion complex and its effect on the absorption of tetramethylpyrazine phosphate in mouse. Chem Pharm Bull. 2012;60(6):736–42.PubMedCrossRefGoogle Scholar
  80. 80.
    Yi T, Tang D, Wang F, Zhang J, Zhang J, Wang J, et al. Enhancing both oral bioavailability and brain penetration of puerarin using borneol in combination with preparation technologies. Drug Deliv. 2017;24(1):422–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Yin QQ, et al. Influence of temperature on transdermal penetration enhancing mechanism of borneol: a multi-scale study. Int J Mol Sci. 2017;18(1)Google Scholar
  82. 82.
    Yin Y, Cao L, Ge H, Duanmu W, Tan L, Yuan J, et al. L-Borneol induces transient opening of the blood-brain barrier and enhances the therapeutic effect of cisplatin. Neuroreport. 2017;28(9):506–13.PubMedCrossRefGoogle Scholar
  83. 83.
    Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.PubMedCrossRefGoogle Scholar
  84. 84.
    Chen JP, et al. Enhancing effect of natural borneol on the cellular uptake of demethoxycurcumin and their combined induction of G2/M arrest in HepG2 cells via ROS generation. J Funct Foods. 2015b;17:103–14.CrossRefGoogle Scholar
  85. 85.
    Chen JP, et al. Synergistic apoptosis-inducing effects on A375 human melanoma cells of natural borneol and curcumin. PLoS One. 2014;9(6)Google Scholar
  86. 86.
    Chen JP, et al. Proteomic analysis of G2/M arrest triggered by natural borneol/curcumin in HepG2 cells, the importance of the reactive oxygen species-p53 pathway. J Agric Food Chem. 2015c;63(28):6440–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen W, Viljoen AM. Geraniol—a review of a commercially important fragrance material. S Afr J Bot. 2010;76(4):643–51.CrossRefGoogle Scholar
  88. 88.
    Cho M, et al. The antitumor effects of geraniol: modulation of cancer hallmark pathways (review). Int J Oncol. 2016;48(5):1772–82.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Bard M, Albrecht MR, Gupta N, Guynn CJ, Stillwell W. Geraniol interferes with membrane functions in strains of Candida and saccharomyces. Lipids. 1988;23(6):534–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Wiseman DA, Werner SR, Crowell PL. Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21(Cip1) and p27(Kip1) in human pancreatic adenocarcinoma cells. J Pharmacol Exp Ther. 2007;320(3):1163–70.PubMedCrossRefGoogle Scholar
  91. 91.
    Yu SG, Hildebrandt LA, Elson CE. Geraniol, an inhibitor of mevalonate biosynthesis, suppresses the growth of hepatomas and melanomas transplanted to rats and mice. J Nutr. 1995;125(11):2763–7.PubMedGoogle Scholar
  92. 92.
    Yu SG, et al. Dietary geraniol suppresses tumor-growth in vivo. FASEB J. 1992a;6(4):A1391.Google Scholar
  93. 93.
    • Hasan SK, Sultana S. Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats. Toxicol Mech Methods. 2015;25(7):559–73. Primary reference for chemoprentative compound reviewed. PubMedGoogle Scholar
  94. 94.
    Cheng HC, Chien H, Liao CH, Yang YY, Huang SY. Carotenoids suppress proliferating cell nuclear antigen and cyclin D-1 expression in oral carcinogenic models. J Nutr Biochem. 2007;18(10):667–75.PubMedCrossRefGoogle Scholar
  95. 95.
    Zahara K, Tabassum S, Sabir S, Arshad M, Qureshi R, Amjad MS, et al. A review of therapeutic potential of Saussurea lappa—an endangered plant from Himalaya. Asian Pac J Trop Med. 2014;7:S60–9.CrossRefGoogle Scholar
  96. 96.
    Gokhale AB, Damre AS, Kulkarni KR, Saraf MN. Preliminary evaluation of anti-inflammatory and anti-arthritic activity of S. lappa, A. speciosa and A. aspera. Phytomedicine. 2002;9(5):433–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Yaeesh S, Jamal Q, Shah AJ, Gilani AH. Antihepatotoxic activity of Saussurea lappa extract on D-galactosamine and lipopolysaccharide-induced hepatitis in mice. Phytother Res. 2010;24:S229–32.PubMedCrossRefGoogle Scholar
  98. 98.
    Kumar A, Kumar S, Kumar D, Agnihotri VK. UPLC/MS/MS method for quantification and cytotoxic activity of sesquiterpene lactones isolated from Saussurea lappa. J Ethnopharmacol. 2014;155(2):1393–7.PubMedCrossRefGoogle Scholar
  99. 99.
    • Dong GZ, Shim AR, Hyeon JS, Lee HJ, Ryu JH. Inhibition of Wnt/-catenin pathway by dehydrocostus lactone and costunolide in colon cancer cells. Phytother Res. 2015;29(5):680–6. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  100. 100.
    Gala MK, Chan AT. Molecular pathways: aspirin and Wnt signaling—a molecularly targeted approach to cancer prevention and treatment. Clin Cancer Res. 2015;21(7):1543–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8(5):387–98.PubMedCrossRefGoogle Scholar
  102. 102.
    Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A, Raz A. Galectin-3, a novel binding partner of beta-catenin. Cancer Res. 2004;64(18):6363–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Gao JM, Wu WJ, Zhang JW, Konishi Y. The dihydro-beta-agarofuran sesquiterpenoids. Nat Prod Rep. 2007;24(5):1153–89.PubMedCrossRefGoogle Scholar
  104. 104.
    Guo J, Yuan SX, Wang XC, Xu SX, LI D. Tripterygium wilfordii Hook f in rheumatoid-arthritis and ankylosing spondylitis. Preliminary report. Chin Med J. 1981;94(7):405–12.PubMedGoogle Scholar
  105. 105.
    Montanari T, Bevilacqua E. Effect of Maytenus ilicifolia Mart. on pregnant mice. Contraception. 2002;65(2):171–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Oliveira MGM, Goldnadel Monteiro M, Macaúbas C, Pereira Barbosa V, Carlini EA. Pharmacological and toxicologic effects of 2 Maytenus species in laboratory-animals. J Ethnopharmacol. 1991;34(1):29–41.PubMedCrossRefGoogle Scholar
  107. 107.
    Perestelo NR, Jiménez IA, Tokuda H, Hayashi H, Bazzocchi IL. Sesquiterpenes from Maytenus jelskii as potential cancer chemopreventive agents. J Nat Prod. 2010;73(2):127–32.PubMedCrossRefGoogle Scholar
  108. 108.
    • Perestelo NR, Jiménez IA, Tokuda H, Vázquez JT, Ichiishi E, Bazzocchi IL. Absolute configuration of dihydro-beta-agarofuran sesquiterpenes from Maytenus jelskii and their potential antitumor-promoting effects. J Nat Prod. 2016;79(9):2324–31. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  109. 109.
    Hsu JL, Glaser SL. Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit Rev Oncol Hematol. 2000;34(1):27–53.PubMedCrossRefGoogle Scholar
  110. 110.
    Ito Y, Yanase S, Fujita J, Harayama T, Takashima M, Imanaka H. A short-term in vitro assay for promoter substances using human-lymphoblastoid cells latently infected with Epstein-Barr virus. Cancer Lett. 1981;13(1):29–37.PubMedCrossRefGoogle Scholar
  111. 111.
    Maimone TJ, Baran PS. Modern synthetic efforts toward biologically active terpenes. Nat Chem Biol. 2007;3(7):396–407.PubMedCrossRefGoogle Scholar
  112. 112.
    Leandro LM, de Sousa Vargas F, Barbosa PCS, Neves JKO, da Silva JA, da Veiga-Junior VF. Chemistry and biological activities of terpenoids from copaiba (Copaifera spp.) oleoresins. Molecules. 2012;17(4):3866–89.PubMedCrossRefGoogle Scholar
  113. 113.
    Santos AO, Ueda-Nakamura T, Dias Filho BP, Veiga Junior VF, Pinto AC, Nakamura CV. Effect of Brazilian copaiba oils on Leishmania amazonensis. J Ethnopharmacol. 2008;120(2):204–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Veiga VF, et al. Chemical composition and anti-inflammatory activity of copaiba oils from Copaifera cearensis Huber ex Ducke, Copaifera reticulata Ducke and Copaifera multijuga Hayne—a comparative study. J Ethnopharmacol. 2007;112(2):248–54.CrossRefGoogle Scholar
  115. 115.
    • Alves JM, Senedese JM, Leandro LF, Castro PT, Pereira DE, Carneiro LJ, et al. Copaifera multijuga oleoresin and its constituent diterpene (−)-copalic acid: genotoxicity and chemoprevention study. Mutat Res. 2017;819:26–30.  Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  116. 116.
    Liao W, McNutt MA, Zhu WG. The comet assay: a sensitive method for detecting DNA damage in individual cells. Methods. 2009;48(1):46–53.PubMedCrossRefGoogle Scholar
  117. 117.
    MacGregor JT, Wehr CM, Gould DH. Clastogen-induced micronuclei in peripheral blood erythrocytes: the basis of an improved micronucleus test. Environ Mutagen. 1980;2(4):509–14.PubMedCrossRefGoogle Scholar
  118. 118.
    Knasmuller S, et al. Search for dietary antimutagens and anticarcinogens: methodological aspects and extrapolation problems. Food Chem Toxicol. 2002;40(8):1051–62.PubMedCrossRefGoogle Scholar
  119. 119.
    Tsai FS, Lin LW, Wu CR. Lupeol and its role in chronic diseases. Adv Exp Med Biol. 2016;929:145–75.PubMedCrossRefGoogle Scholar
  120. 120.
    Siddique HR, Saleem M. Beneficial health effects of lupeol triterpene: a review of preclinical studies. Life Sci. 2011;88(7–8):285–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Sultana S, Saleem M, Sharma S, Khan N. Lupeol, a triterpene, prevents free radical mediated macromolecular damage and alleviates benzoyl peroxide induced biochemical alterations in murine skin. Indian J Exp Biol. 2003;41(8):827–31.PubMedGoogle Scholar
  122. 122.
    Yasukawa K, Yu SY, Yamanouchi S, Takido M, Akihisa T, Tamura T. Some lupane-type triterpenes inhibit tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Phytomedicine. 1995;1(4):309–13.PubMedCrossRefGoogle Scholar
  123. 123.
    Manoharan S, Palanimuthu D, Baskaran N, Silvan S. Modulating effect of lupeol on the expression pattern of apoptotic markers in 7, 12-dimethylbenz(a)anthracene induced oral carcinogenesis. Asian Pac J Cancer Prev. 2012;13(11):5753–7.PubMedCrossRefGoogle Scholar
  124. 124.
    Nigam N, Prasad S, Shukla Y. Preventive effects of lupeol on DMBA induced DNA alkylation damage in mouse skin. Food Chem Toxicol. 2007;45(11):2331–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Palanimuthu D, Baskaran N, Silvan S, Rajasekaran D, Manoharan S. Lupeol, a bioactive triterpene, prevents tumor formation during 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis. Pathol Oncol Res. 2012;18(4):1029–37.PubMedCrossRefGoogle Scholar
  126. 126.
    Prasad S, Kumar Yadav V, Srivastava S, Shukla Y. Protective effects of lupeol against benzo a pyrene induced clastogenicity in mouse bone marrow cells. Mol Nutr Food Res. 2008;52(10):1117–20.PubMedCrossRefGoogle Scholar
  127. 127.
    Saleem M, Afaq F, Adhami VM, Mukhtar H. Lupeol modulates NF-kappa B and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene. 2004;23(30):5203–14.PubMedCrossRefGoogle Scholar
  128. 128.
    Saleem M, Alam A, Arifin S, Shah MS, Ahmed B, Sultana S. Lupeol, a triterpene, inhibits early responses of tumor promotion induced by benzoyl peroxide in murine skin. Pharmacol Res. 2001;43(2):127–34.PubMedCrossRefGoogle Scholar
  129. 129.
    Chaturvedi PK, Bhui K, Shukla Y. Lupeol: connotations for chemoprevention. Cancer Lett. 2008;263(1):1–13.PubMedCrossRefGoogle Scholar
  130. 130.
    • Prabhu B, Balakrishnan D, Sundaresan S. Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats. Hum Exp Toxicol. 2016;35(6):685–92. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  131. 131.
    Wanibuchi H, Yamamoto S, Chen H, Yoshida K, Endo G, Hori T, et al. Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis. 1996;17(11):2435–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Getzenberg RH, Konety BR, Oeler TA, Quigley MM, Hakam A, Becich MJ, et al. Bladder cancer-associated nuclear matrix proteins. Cancer Res. 1996;56(7):1690–4.PubMedGoogle Scholar
  133. 133.
    Hammam OA, Aziz AA, Roshdy MS, Abdel Hadi AM. Possible role of cyclooxygenase-2 in schistosomal and non-schistosomal-associated bladder cancer. Medscape J Med. 2008;10(3):60.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Pirtskalaishvili G, Getzenberg RH, Konety BR. Use of urine-based markers for detection and monitoring of bladder cancer. Tech Urol. 1999;5(4):179–84.PubMedGoogle Scholar
  135. 135.
    • Singh P, Arora D, Shukla Y. Enhanced chemoprevention by the combined treatment of pterostilbene and lupeol in B a P-induced mouse skin tumorigenesis. Food Chem Toxicol. 2017;99:182–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Langcake P, Cornford CA, Pryce RJ. Identification of pterostilbene as a phytoalexin from Vitis vinifera leaves. Phytochemistry. 1979;18(6):1025–7.CrossRefGoogle Scholar
  137. 137.
    Jang MS, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218–20.PubMedCrossRefGoogle Scholar
  138. 138.
    Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2–3):97–110.PubMedCrossRefGoogle Scholar
  139. 139.
    Tarapore RS, Siddiqui IA, Adhami VM, Spiegelman VS, Mukhtar H. The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/beta-catenin signaling. Mol Nutr Food Res. 2013;57(11):1950–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008;22(6):709–24.PubMedCrossRefGoogle Scholar
  141. 141.
    Van Rossum TGJ, et al. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. J Gastroenterol Hepatol. 1999;14(11):1093–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Vlietinck AJ, et al. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection. Planta Med. 1998;64(2):97–109.PubMedCrossRefGoogle Scholar
  143. 143.
    • Hasan SK, Khan R, Ali N, Khan AQ, Rehman MU, Tahir M, et al. 18-Glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats: role in hyperproliferation, inflammation and oxidative stress. Hum Exp Toxicol. 2015;34(6):628–41. Primary reference for chemoprentative compound reviewed. PubMedCrossRefGoogle Scholar
  144. 144.
    Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245(3):194–205.PubMedCrossRefGoogle Scholar
  145. 145.
    Blokhina O, Virolainen E, Fagerstedt KV. Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot. 2003;91(2):179–94.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Yu CCW, Woods AL, Levison DA. The assessment of cellular proliferation by immunohistochemistry—a review of currently available methods and their applications. Histochem J. 1992b;24(3):121–31.PubMedCrossRefGoogle Scholar
  147. 147.
    Yuan JP, Peng J, Yin K, Wang JH. Potential health-promoting effects of astaxanthin: a high-value carotenoid mostly from microalgae. Mol Nutr Food Res. 2011;55(1):150–65.PubMedCrossRefGoogle Scholar
  148. 148.
    Kidd P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev. 2011;16(4):355–64.PubMedGoogle Scholar
  149. 149.
    Tanaka T, Kawamori T, Ohnishi M, Makita H, Mori H, Satoh K, et al. Suppression of azoxymethane-induced rat colon carcinogenesis by dietary administration of naturally occurring xanthophylls astaxanthin and canthaxanthin during the postinitiation phase. Carcinogenesis. 1995;16(12):2957–63.PubMedCrossRefGoogle Scholar
  150. 150.
    Tanaka T, Makita H, Ohnishi M, Mori H, Satoh K, Hara A. Chemoprevention of rat oral carcinogenesis by naturally occurring xanthophylls, astaxanthin and canthaxarathin. Cancer Res. 1995;55(18):4059–64.PubMedGoogle Scholar
  151. 151.
    Tanaka T, Morishita Y, Suzui M, Kojima T, Okumura A, Mori H. Chemoprevention of mouse urinary bladder carcinogenesis by the naturally-occurring carotenoid astaxanthin. Carcinogenesis. 1994;15(1):15–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Tanaka T, Shnimizu M, Moriwaki H. Cancer chemoprevention by carotenoids. Molecules. 2012;17(3):3202–42.PubMedCrossRefGoogle Scholar
  153. 153.
    Yasui Y, Hosokawa M, Mikami N, Miyashita K, Tanaka T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem Biol Interact. 2011;193(1):79–87.PubMedCrossRefGoogle Scholar
  154. 154.
    Ishino K, Mutoh M, Totsuka Y, Nakagama H. Metabolic syndrome: a novel high-risk state for colorectal cancer. Cancer Lett. 2013;334(1):56–61.PubMedCrossRefGoogle Scholar
  155. 155.
    Giovannucci E. Insulin and colon cancer. Cancer Causes Control. 1995;6(2):164–79.PubMedCrossRefGoogle Scholar
  156. 156.
    Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon-cancer and adenoma in men. Ann Intern Med. 1995;122(5):327–34.PubMedCrossRefGoogle Scholar
  157. 157.
    Perse M. Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int. 2013;Google Scholar
  158. 158.
    • Kochi T, et al. Inhibitory effects of astaxanthin on azoxymethane-induced colonic preneoplastic lesions in C57/BL/KsJ-db/db mice. BMC Gastroenterol. 2014;14:10.  Primary reference for chemoprentative compound reviewed. CrossRefGoogle Scholar
  159. 159.
    Lamont JT, Ogorman TA. Experimental colon cancer. Gastroenterology. 1978;75(6):1157–69.PubMedGoogle Scholar
  160. 160.
    Fellmann L, Nascimento AR, Tibiriça E, Bousquet P. Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther. 2013;137(3):331–40.PubMedCrossRefGoogle Scholar
  161. 161.
    Hirose Y, Hata K, Kuno T, Yoshida K, Sakata K, Yamada Y, et al. Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Carcinogenesis. 2004;25(5):821–5.PubMedCrossRefGoogle Scholar
  162. 162.
    Hayashi I, Morishita Y, Imai K, Nakamura M, Nakachi K, Hayashi T. High-throughput spectrophotometric assay of reactive oxygen species in serum. Mutat Res-Genet Toxicol Environ Mutagen. 2007;631(1):55–61.CrossRefGoogle Scholar
  163. 163.
    Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 2004;339(1–2):1–9.PubMedCrossRefGoogle Scholar
  164. 164.
    Arunkumar E, Bhuvaneswari S, Anuradha CV. An intervention study in obese mice with astaxanthin, a marine carotenoid—effects on insulin signaling and pro-inflammatory cytokines. Food Funct. 2012;3(2):120–6.PubMedCrossRefGoogle Scholar
  165. 165.
    Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84.PubMedCrossRefGoogle Scholar
  166. 166.
    Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1–40.PubMedCrossRefGoogle Scholar
  167. 167.
    Craig WJ, Mangels AR, Ada. Position of the American Dietetic Association: vegetarian diets. J Am Diet Assoc. 2009;109(7):1266–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Medicine, Pennsylvania State University College of MedicineThe Penn State Cancer InstituteHersheyUSA

Personalised recommendations