Targeting Cellular Signaling for Cancer Prevention and Therapy by Phytochemicals

  • Fang Hao
  • Neelu Yadav
  • Dhyan Chandra


Phytochemicals are plant-derived compounds and have been considered as promising chemopreventive agents for decades. Phytochemicals are broadly classified as carotenoids, phenolics, alkaloids, nitrogen-containing compounds, and organosulfur compounds. These plant-derived compounds modulate the hallmark events in tumorigenesis including the control of cellular redox, cell proliferation and death, angiogenesis, and cell migration. Preclinical studies on a number of phytochemicals in mouse models support anticancer activities of these compounds. Clinical studies of some phytochemicals reveal inconsistency with preclinical findings, thus highlighting the necessity of detailed in vivo analysis of the mechanism of action of these compounds prior to initiate large-scale clinical trials. This chapter describes some of the key molecular cellular signaling that could be targeted to utilize full benefits of these phytochemicals for cancer prevention and therapy.


Apoptosis Mitochondria Autophagy Phytochemicals Angiogenesis Cellular redox Reactive oxygen species (ROS) Cell proliferation Cell migration and invasion Lycopene β-Carotene Clinical trials Resveratrol Neem limonoids 



This work was supported in part by the National Cancer Institute of the National Institutes of Health under Award Number R01CA160685 and the American Cancer Society Research Scholar Grant RSG-12-214-01– CCG to DC; and the National Cancer Institute Center Support Grant P30 CA016056 to the Roswell Park Cancer Institute. We apologize to those colleagues whose publications could not be cited due to space constraints.


  1. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards B, Haapakoski J, Rautalahti M, Hartman A, Palmgren J (1995) Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the alpha-tocopherol beta-carotene cancer prevention study. Am J Clin Nutr 62:1427S–1430SPubMedGoogle Scholar
  2. Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J (1996) α-Tocopherol and β-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 88:1560–1570PubMedCrossRefGoogle Scholar
  3. Albanes D, Virtamo J, Taylor P, Rautalahti M, Pietinen P, Heinonen O (1997) Effects of supplemental beta-carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the alpha-tocopherol, beta-carotene cancer prevention study. Am J Clin Nutr 66:366–372PubMedGoogle Scholar
  4. Albanes D, Malila N, Taylor PR, Huttunen JK, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Barrett MJ, Pietinen P (2000) Effects of supplemental α-tocopherol and β-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes and Control 11:197–205PubMedCrossRefGoogle Scholar
  5. Astorg P, Gradelet S, Bergès R, Suschetet M (1997) Dietary lycopene decreases the initiation of liver preneoplastic foci by diethylnitrosamine in the rat. Nutr Cancer 29(1):60–68PubMedCrossRefGoogle Scholar
  6. Balasenthil S, Arivazhagan S, Ramachandran C, Ramachandran V, Nagini S (1999) Chemopreventive potential of neem (Azadirachta indica) on 7, 12-dimethylbenz [a] anthracene (DMBA) induced hamster buccal pouch carcinogenesis. J Ethnopharmacol 67:189–195PubMedCrossRefGoogle Scholar
  7. Ben-Dor A, Nahum A, Danilenko M, Giat Y, Stahl W, Martin H-D, Emmerich T, Noy N, Levy J, Sharoni Y (2001) Effects of acyclo-retinoic acid and lycopene on activation of the retinoic acid receptor and proliferation of mammary cancer cells. Arch Biochem Biophys 391:295–302PubMedCrossRefGoogle Scholar
  8. Ben-Dor A, Steiner M, Gheber L, Danilenko M, Dubi N, Linnewiel K, Zick A, Sharoni Y, Levy J (2005) Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther 4:177–186PubMedGoogle Scholar
  9. Bendich A, Olson JA (1989) Biological actions of carotenoids. The FASEB Journal 3:1927–32Google Scholar
  10. Bensaad K, Tsuruta A, Selak MA, Vidal M, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120PubMedCrossRefGoogle Scholar
  11. Block G, Patterson B, Subar A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 18:1–29PubMedCrossRefGoogle Scholar
  12. Burton GW, Ingold KU (1984) beta-Carotene: an unusual type of lipid antioxidant. Science 224:569–73PubMedCrossRefGoogle Scholar
  13. Campello S, Lacalle RA, Bettella M, Mañes S, Scorrano L, Viola A (2006) Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med 203:2879–2886Google Scholar
  14. Chandra D, Singh KK (2011) Genetic insights into OXPHOS defect and its role in cancer. Biochim Biophys Acta 1807:620–5PubMedCrossRefGoogle Scholar
  15. Chang C-J, Yin P-H, Yang D-M, Wang C-H, Hung W-Y, Chi C-W, Wei Y-H, Lee H-C (2009) Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell Mol Life Sci 66:1755–1765CrossRefGoogle Scholar
  16. Compton S, Kim C, Griner NB, Potluri P, Scheffler IE, Sen S, Jerry DJ, Schneider S, Yadava N (2011) Mitochondrial dysfunction impairs tumor suppressor p53 expression/function. J Biol Chem 286:20297–312PubMedCrossRefGoogle Scholar
  17. Cook NR, Lee I-M, Manson JE, Buring JE, Hennekens CH (2000) Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians’ Health Study (United States). Cancer Causes and Control 11:617–626Google Scholar
  18. Dasgupta T, Banerjee S, Yadava P, Rao A (2004) Chemopreventive potential of Azadirachta indica (Neem) leaf extract in murine carcinogenesis model systems. J Ethnopharmacol 92:23–36PubMedCrossRefGoogle Scholar
  19. Daviglus ML, Dyer AR, Persky V, Chavez N, Drum M, Goldberg J, Liu K, Morris DK, Shekelle RB, Stamler J (1996) Dietary beta-carotene, vitamin C, and risk of prostate cancer: results from the western electric study. Epidemiology 7(5) 472–477PubMedCrossRefGoogle Scholar
  20. Demmig-Adams B, Adams WW (2002) Antioxidants in Photosynthesis and Human Nutrition. Science 298:2149–2153PubMedCrossRefGoogle Scholar
  21. Di Mascio P, Kaiser S, Sies H (1989) Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 274:532–538PubMedCrossRefGoogle Scholar
  22. Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S (2010) Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer 127:172–184PubMedCrossRefGoogle Scholar
  23. Elumalai P, Gunadharini D, Senthilkumar K, Banudevi S, Arunkumar R, Benson C, Sharmila G, Arunakaran J (2012) Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. Toxicol Lett 215(2):131–42PubMedCrossRefGoogle Scholar
  24. Franceschi S, Favero A, La Vecchia C, Negri E, Conti E, Montella M, Giacosa A, Nanni O, Decarli A (1998) Food groups and risk of colorectal cancer in Italy. Int J Cancer 72:56–61CrossRefGoogle Scholar
  25. Freudenhiem JL, Graham S Marshalljr, BP Haughey, G Wilkinson (1990) A case-control study of diet and rectal cancer in western New York. Am J Epidemiol 131:612–624Google Scholar
  26. Frieling UM, Schaumberg DA, Kupper TS, Muntwyler J, Hennekens CH (2000) A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the Physicians’ Health Study. Arch Dermatol 136:179–184PubMedGoogle Scholar
  27. Galluzzi L, Kepp O, Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 13:780–788PubMedCrossRefGoogle Scholar
  28. Gogada R, Prabhu V, Amadori M, Scott R, Hashmi S, Chandra D (2011) Resveratrol induces p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated Bax protein oligomerization on mitochondria to initiate cytochrome c release and caspase activation. J Biol Chem 286:28749–28760PubMedCrossRefGoogle Scholar
  29. Goo YA, Li Z, Pajkovic N, Shaffer S, Taylor G, Chen J, Campbell D, Arnstein L, Goodlett DR, Breemen RB van (2007) Systematic investigation of lycopene effects in LNCaP cells by use of novel large-scale proteomic analysis software. Proteomics Clin Appl 1:513–523PubMedCrossRefGoogle Scholar
  30. Goodman GE, Schaffer S, Omenn GS, Chen C, King I (2003) The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from β-carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev 12:518–526PubMedGoogle Scholar
  31. Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens Jr FL, Omenn GS, Valanis B, Williams Jr JH (2004) The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping β-carotene and retinol supplements. J Natl Cancer Inst 96:1743–1750PubMedCrossRefGoogle Scholar
  32. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906PubMedCrossRefGoogle Scholar
  33. Gradelet S, Astorg P, Leclerc J, Chevalier J, Vernevaut M, Siess M-H (1996a) Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat. Xenobiotica 26:49–63CrossRefGoogle Scholar
  34. Gradelet S, Leclerc J, Siess M-H, Astorg PO (1996b) β-Apo-8’²-carotenal, but not β-carotene, is a strong inducer of liver cytochromes P4501A1 and 1A2 in rat. Xenobiotica 26:909–919CrossRefGoogle Scholar
  35. Group ACPS (1994) The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann Epidemiol 4:1–10CrossRefGoogle Scholar
  36. Gu M, Singh RP, Dhanalakshmi S, Agarwal C, Agarwal R (2007) Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice. Cancer Res 67:3483–3491PubMedCrossRefGoogle Scholar
  37. Gunadharini DN, Elumalai P, Arunkumar R, Senthilkumar K, Arunakaran J (2011) Induction of apoptosis and inhibition of PI3K/Akt pathway in PC-3 and LNCaP prostate cancer cells by ethanolic neem leaf extract. J Ethnopharmacol 134:644–650PubMedCrossRefGoogle Scholar
  38. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70Google Scholar
  39. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  40. Handelman GJ, Packer L, Cross CE (1996) Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke. Am J Clin Nutr 63:559–565Google Scholar
  41. Hantz HL, Young LF, Martin KR (2005) Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med 230:171–179Google Scholar
  42. Harish Kumar G, Chandra Mohan K, Jagannadha Rao A, Nagini S (2009) Nimbolide a limonoid from Azadirachta indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells. Invest New Drugs 27:246–252PubMedCrossRefGoogle Scholar
  43. Heinonen OP, Koss L, Albanes D, Taylor PR, Hartman AM, Edwards BK, Virtamo J, Huttunen JK, Haapakoski J, Malila N (1998) Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 90:440–446PubMedCrossRefGoogle Scholar
  44. Helzlsouer KJ, Comstock GW, Morris JS (1989) Selenium, Lycopene, α-Tocopherol, β-Carotene, Retinol, and Subsequent Bladder Cancer. Cancer Res 49:6144–6148PubMedGoogle Scholar
  45. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334:1145–1149PubMedCrossRefGoogle Scholar
  46. Holick CN, Michaud DS, Stolzenberg-Solomon R, Mayne ST, Pietinen P, Taylor PR, Virtamo J, Albanes D (2002) Dietary carotenoids, serum β-carotene, and retinol and risk of lung cancer in the Alpha-Tocopherol, Beta-Carotene cohort study. Am J Epidemiol 156:536–547Google Scholar
  47. Hu J, Liu Y Yuy, T Zhao, S Liu, Q Wang (1991) Diet and cancer of the colon and rectum: a case-control study in China. Int J Epidemiol 20:362–367PubMedCrossRefGoogle Scholar
  48. Huncharek M, Klassen H, Kupelnick B (2001) Dietary beta-carotene intake and the risk of epithelial ovarian cancer: a meta-analysis of 3,782 subjects from five observational studies. In vivo (Athens, Greece) 15:339–343PubMedGoogle Scholar
  49. Hung W-Y, Huang K-H, Wu C-W, Chi C-W, Kao H-L, Li AF-Y, Yin P-H, Lee H-C (2012) Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells. Biochimica et Biophysica Acta (BBA)-General Subjects 1820:1102–1110Google Scholar
  50. Hwang E-S, Bowen PE (2004) Cell cycle arrest and induction of apoptosis by lycopene in LNCaP human prostate cancer cells. J Med Food 7:284–289PubMedCrossRefGoogle Scholar
  51. Hwang ES, Bowen PE. (2005) Effects of lycopene and tomato paste extracts on DNA and lipid oxidation in LNCaP human prostate cancer cells. BioFactors 23:97–105Google Scholar
  52. Ilio VD, Pasquariello N, Esch ASvd, Cristofaro M, Scarsella G, Risuleo G (2006) Cytotoxic and antiproliferative effects induced by a non terpenoid polar extract of A. indica seeds on 3T6 murine fibroblasts in culture. Mol Cell Biochem 287:69–77PubMedCrossRefGoogle Scholar
  53. Ivanov NI, Cowell SP, Brown P, Rennie PS, Guns ES, Cox ME (2007) Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr (Edinburgh, Scotland) 26:252–263PubMedCrossRefGoogle Scholar
  54. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23:537–548PubMedCrossRefGoogle Scholar
  55. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039PubMedCrossRefGoogle Scholar
  56. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng H-YM, Ravagnan L (2001) Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410:549–554PubMedCrossRefGoogle Scholar
  57. Kanagaraj P, Vijayababu M, Ravisankar B, Anbalagan J, Aruldhas M, Arunakaran J (2007) Effect of lycopene on insulin-like growth factor-I, IGF binding protein-3 and IGF type-I receptor in prostate cancer cells. J Cancer Res Clin Oncol 133:351–359PubMedCrossRefGoogle Scholar
  58. Karas M, Amir H, Fishman D, Danilenko M, Segal S, Nahum A, Koifmann A, Giat Y, Levy J, Sharoni Y (2000) Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer 36:101–111PubMedCrossRefGoogle Scholar
  59. Karppi J, Kurl S, Laukkanen JA, Kauhanen J (2012) Serum β-carotene in relation to risk of prostate cancer: the kuopio ischaemic heart disease risk factor study. Nutr Cancer 64:361–367PubMedCrossRefGoogle Scholar
  60. Kavitha K, Vidya Priyadarsini R, Anitha P, Ramalingam K, Sakthivel R, Purushothaman G, Singh AK, Karunagaran D, Nagini S (2012) Nimbolide, a neem limonoid abrogates canonical NF-κB and Wnt signaling to induce caspase-dependent apoptosis in human hepatocarcinoma (HepG2) cells. Eur J Pharmacol 681(1–3):6–14PubMedCrossRefGoogle Scholar
  61. Kikuchi T, Ishii K, Noto T, Takahashi A, Tabata K, Suzuki T, Akihisa T (2011) Cytotoxic and apoptosis-inducing activities of limonoids from the seeds of Azadirachta indica (neem). J Natural Prod 74:866–870CrossRefGoogle Scholar
  62. Kim L, Rao AV, Rao LG (2002) Effect of lycopene on prostate LNCaP cancer cells in culture. J Med Food 5:181–187PubMedCrossRefGoogle Scholar
  63. Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U (2006) Supplemental and dietary vitamin E, β-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst 98:245–254PubMedCrossRefGoogle Scholar
  64. Kong A-NT, Owuor E, Yu R, Hebbar V, Chen C, Hu R, Mandlekar S (2001) Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab Rev 33:255–271Google Scholar
  65. Krinsky NI, Johnson EJ (2005) Carotenoid actions and their relation to health and disease. Mol Aspects Med 26:459–516PubMedCrossRefGoogle Scholar
  66. Kunimasa K, Ohta T, Tani H, Kato E, Eguchi R, Kaji K, Ikeda K, Mori H, Mori M, Tatefuji T (2011) Resveratrol derivative-rich melinjo (Gnetum gnemon L.) seed extract suppresses multiple angiogenesis-related endothelial cell functions and tumor angiogenesis. Mol Nutr Food Res 55:1730–1734PubMedCrossRefGoogle Scholar
  67. Kusamran W, Ratanavila A, Tepsuwan A (1998) Effects of neem flowers, thai and chinese bitter gourd fruits and sweet basil leaves on hepatic monooxygenases and glutathiones-transferase activities, and in vitro metabolic activation of chemical carcinogens in rats. Food Chem Toxicol 36:475–484PubMedCrossRefGoogle Scholar
  68. Lee CH, Wu SB, Hong CH, Liao WT, Wu CY, Chen GS, Wei YH, Yu HS (2011) Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers. Am J Pathol 178:2066–76PubMedCrossRefGoogle Scholar
  69. Lee E-O, Lee H-J, Hwang H-S, Ahn K-S, Chae C, Kang K-S, Lu J, Kim S-H (2006) Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis 27:2059–2069PubMedCrossRefGoogle Scholar
  70. Lee I-M, Cook NR, Manson JE, Buring JE, Hennekens CH (1999) β-Carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. J Natl Cancer Inst 91:2102–2106PubMedCrossRefGoogle Scholar
  71. Lenaz G (2012) Mitochondria and Reactive Oxygen Species. Which Role in Physiology and Pathology? In: Scatena R, Bottoni P, Giardina B (eds) Advances in Mitochondrial Medicine. Springer Netherlands 942:93–136Google Scholar
  72. Lin C-C, Tsai Y-L, Huang M-T, Lu Y-P, Ho C-T, Tseng S-F, Teng S-C (2006) Inhibition of estradiol-induced mammary proliferation by dibenzoylmethane through the E2–ER–ERE-dependent pathway. Carcinogenesis 27:131–136PubMedCrossRefGoogle Scholar
  73. Lin M-C, Wang F-Y, Kuo Y-H, Tang F-Y (2011) Cancer chemopreventive effects of lycopene: suppression of MMP-7 expression and cell invasion in human colon cancer cells. J Agric Food Chem 59:11304–11318PubMedCrossRefGoogle Scholar
  74. Lin HX, Qiu HJ, Zeng F, Rao HL, Yang GF, Kung HF, Zhu XF, Zeng YX, Cai MY, Xie D (2013) Decreased expression of Beclin 1 correlates closely with Bcl-xL expression and poor prognosis of ovarian carcinoma. PLoS One 8:e60516PubMedCrossRefGoogle Scholar
  75. Lin X, Wu G, Huo WQ, Zhang Y, Jin FS (2012) Resveratrol induces apoptosis associated with mitochondrial dysfunction in bladder carcinoma cells. Int J Urol 19(8):757–764PubMedCrossRefGoogle Scholar
  76. Liu C, Wang X-D, Bronson RT, Smith DE, Krinsky NI, Russell RM (2000) Effects of physiological versus pharmacological β-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. Carcinogenesis 21:2245–2253PubMedCrossRefGoogle Scholar
  77. Luo C, Wu X-G (2011) Lycopene enhances antioxidant enzyme activities and immunity function in N-Methyl-N†²-nitro-N-nitrosoguanidine–induced gastric cancer rats. Int J Mol Sci 12:3340–3351PubMedCrossRefGoogle Scholar
  78. Mahapatra S, Karnes RJ, Holmes MW, Young CY, Cheville JC, Kohli M, Klee EW, Tindall DJ, Donkena KV (2011) Novel molecular targets of Azadirachta indica associated with inhibition of tumor growth in prostate cancer. AAPS J 13:365–377PubMedCrossRefGoogle Scholar
  79. Mahapatra S, Young CY, Kohli M, Karnes RJ, Klee EW, Holmes MW, Tindall DJ, Donkena KV (2012) Antiangiogenic effects and therapeutic targets of azadirachta indica leaf extract in endothelial cells. Evidence-Based Complementary and Alternative Medicine 2012Google Scholar
  80. Malila N, Taylor PR, Virtanen MJ, Korhonen P, Huttunen JK, Albanes D, Virtamo J (2002a) Effects of alpha-tocopherol and beta-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland). Cancer Causes and Control 13:617–623PubMedCrossRefGoogle Scholar
  81. Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L (2002b) Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Eur J Clin Nutr 56:615–621Google Scholar
  82. Manikandan P, Letchoumy PV, Gopalakrishnan M, Nagini S (2008) Evaluation of Azadirachta indica leaf fractions for in vitro antioxidant potential andin vivo modulation of biomarkers of chemoprevention in the hamster buccal pouch carcinogenesis model. Food Chem Toxicol 46:2332–2343PubMedCrossRefGoogle Scholar
  83. Manikandan P, Murugan RS, Vinothini G, Priyadarsini RV, Singh IP, Anandan R, Gopalakrishnan M, Nagini S (2012) Investigation of the chemopreventive potential of neem leaf subfractions in the hamster buccal pouch model and phytochemical characterization. Eur J Med Chem 56:271–281PubMedCrossRefGoogle Scholar
  84. Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, Galarreta CMR de, Cuadrado A (2004) Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem 279:8919–8929PubMedCrossRefGoogle Scholar
  85. Mathew R, White E (2011) Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev 21:113–9PubMedCrossRefGoogle Scholar
  86. Matoba S, Kang J-G, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science Signalling 312:1650–1653Google Scholar
  87. Mayne ST, Handelman GJ, Beecher G (1996) Beta-Carotene and lung cancer promotion in heavy smokers–a plausible relationship? J Natl Cancer Inst 88:1513PubMedGoogle Scholar
  88. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R60PubMedCrossRefGoogle Scholar
  89. Michiels C, Raes M, Toussaint O, Remacle J (1994) Importance of SE-glutathione peroxidase, catalase, and CU/ZN-SOD for cell survival against oxidative stress. Free Radic Biol Med 17:235–248PubMedCrossRefGoogle Scholar
  90. Mousa SS, Mousa SS, Mousa SA (2005) Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model. Nutr Cancer 52:59–65PubMedCrossRefGoogle Scholar
  91. Nagel G, Linseisen J, Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A, Roswall N, Witt PM, Overvad K, Rohrmann S, Kaaks R, Drogan D, Boeing H, Trichopoulou A, Stratigakou V, Zylis D, Engeset D, Lund E, Skeie G, Berrino F, Grioni S, Mattiello A, Masala G, Tumino R, Zanetti R, Ros MM, Bueno-de-Mesquita HB, Ardanaz E, Sánchez MJ, Huerta JM, Amiano P, Rodríguez L, Manjer J, Wirfält E, Lenner P, Hallmans G, Spencer EA, Key TJ, Bingham S, Khaw KT, Rinaldi S, Slimani N, Boffetta P, Gallo V, Norat T, Riboli E (2010) Dietary β-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat 119:753–765PubMedCrossRefGoogle Scholar
  92. Nahum A, Hirsch K, Danilenko M, Watts C, Prall O, Levy J, Sharoni Y (2001) Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27 (Kip1) in the cyclin E-cdk2 complexes. Oncogene 20:3428–3436PubMedCrossRefGoogle Scholar
  93. Nahum A, Zeller L, Danilenko M, Prall OW, Watts CK, Sutherland RL, Levy J, Sharoni Y (2006) Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1. Eur J Nutr 45:275–282PubMedCrossRefGoogle Scholar
  94. Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE (2003) Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the β-Carotene and retinol efficacy trial (CARET). Cancer Epidemiol Biomarkers Prev 12:350–358PubMedGoogle Scholar
  95. Nierenberg DW, Nann SL (1992) A method for determining concentrations of retinol, tocopherol, and five carotenoids in human plasma and tissue samples. The Am J Clin Nutr 56:417–26Google Scholar
  96. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens Jr FL, Valanis B, Williams Jr JH (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334:1150–1155PubMedCrossRefGoogle Scholar
  97. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275:21797–21800PubMedCrossRefGoogle Scholar
  98. Palan PR, Chang CJ, Mikhail MS, Ho GYF, Basu J, Romney SL (1998) Plasma concentrations of micronutrients during α nine-month clinical trial of β-carotene in women with precursor cervical cancer lesions. Nutr Cancer 30:46–52PubMedCrossRefGoogle Scholar
  99. Palozza P, Colangelo M, Simone R, Catalano A, Boninsegna A, Lanza P, Monego G, Ranelletti FO (2010) Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 31:1813–1821PubMedCrossRefGoogle Scholar
  100. Park YOH, Hwang ES, Moon TW (2005) The effect of lycopene on cell growth and oxidative DNA damage of Hep3B human hepatoma cells. Biofactors 23:129–139PubMedCrossRefGoogle Scholar
  101. Pelicano H, Lu W, Zhou Y, Zhang W, Chen Z, Hu Y, Huang P (2009) Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism. Cancer Res 69:2375–2383PubMedCrossRefGoogle Scholar
  102. Prabhu V, Srivastava P, Yadav N, Amadori M, Schneider A, Seshadri A, Pitaressi J, Scott R, Zhang H, Koochekpour S (2012) Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation. Mitochondrion 13(5):493–499PubMedCrossRefGoogle Scholar
  103. Priyadarsini RV, Manikandan P, Kumar GH, Nagini S (2009) The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis. Free Radic Res 43:492–504PubMedCrossRefGoogle Scholar
  104. Priyadarsini RV, Murugan RS, Sripriya P, Karunagaran D, Nagini S (2010) The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells. Free Radic Res 44:624–634PubMedCrossRefGoogle Scholar
  105. Ratke J, Entschladen F, Niggemann B, Zänker KS, Lang K (2010) Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways. Endocrine-related Cancer 17:179–189Google Scholar
  106. Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–90PubMedCrossRefGoogle Scholar
  107. Raza H (2011) Dual localization of glutathione S-transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease. FEBS J 278(22):4243–4251PubMedCrossRefGoogle Scholar
  108. Ricci F, Berardi V, Risuleo G (2008) Differential cytotoxicity of MEX: a component of Neem oil whose action is exerted at the cell membrane level. Molecules 14:122–132PubMedCrossRefGoogle Scholar
  109. Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Tsushida T (2006) Inhibition of colon cancer (HT-29) cell proliferation by a triterpenoid isolated from Azadirachta indica is accompanied by cell cycle arrest and up-regulation of p21. Planta medica 72:917–923PubMedCrossRefGoogle Scholar
  110. Sangar MC, Bansal S, Avadhani NG (2010) Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity. Expert Opin Drug Metab Toxicol 6:1231–1251PubMedCrossRefGoogle Scholar
  111. Satia JA, Littman A, Slatore CG, Galanko JA, White E (2009) Long-term Use of β-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study. Am J Epidemiol 169:815–828PubMedCrossRefGoogle Scholar
  112. Schumacher M, Cerella C, Reuter S, Dicato M, Diederich M (2011) Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway. Genes Nutr 6:149–160PubMedCrossRefGoogle Scholar
  113. Scolastici C, Alves deLRO, Barbisan LF, Ferreira ALA, Ribeiro DA, Salvadori DMF (2008) Antigenotoxicity and antimutagenicity of lycopene in HepG2 cell line evaluated by the comet assay and micronucleus test. Toxicol In Vitro 22:510–514PubMedCrossRefGoogle Scholar
  114. Semenza GL, Roth PH, Fang H-M, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763PubMedGoogle Scholar
  115. Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48(2):158–167Google Scholar
  116. Seren S, Lieberman R, Bayraktar UD, Heath E, Sahin K, Andic F, Kucuk O (2008) Lycopene in cancer prevention and treatment. Am J Ther 15:66–81PubMedCrossRefGoogle Scholar
  117. Sherwood LM, Parris EE, Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186CrossRefGoogle Scholar
  118. Sheweita SA (2000) Drug-metabolizing enzymes mechanisms and functions. Curr Drug Metab 1:107–132PubMedCrossRefGoogle Scholar
  119. Shim H, Dolde C, Lewis BC, Wu C-S, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci 94:6658–6663PubMedCrossRefGoogle Scholar
  120. Skoda RC, Demierre A, McBride OW, Gonzalez FJ, Meyer UA (1988) Human microsomal xenobiotic epoxide hydrolase. Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization. J Biol Chem 263:1549–1554PubMedGoogle Scholar
  121. Srivastava P, Yadav N, Lella R, Schneider A, Jones A, Marlowe T, Lovett G, O’Loughlin K, Minderman H, Gogada R (2012) Neem oil limonoids induces p53-independent apoptosis and autophagy. Carcinogenesis 33(11):2199–2207PubMedCrossRefGoogle Scholar
  122. Stich HF, Hornby AP, Dunn BP (1986) Beta-carotene levels in exfoliated mucosa cells of population groups at low and elevated risk for oral cancer. Int J Cancer 37:389–393Google Scholar
  123. Stram DO, Huberman M, Wu AH (2002) Is residual confounding a reasonable explanation for the apparent protective effects of beta-carotene found in epidemiologic studies of lung cancer in smokers? Am J Epidemiol 155:622–628PubMedCrossRefGoogle Scholar
  124. Stryker WS, Kaplan LA, Stein EA, Stampfer MJ, Sober A, Willett WC (1988) The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am J Epidemiol 127:283–296PubMedGoogle Scholar
  125. Subapriya R, Kumaraguruparan R, Abraham S, Nagini S (2004) Protective effects of ethanolic neem leaf extract on N-methyl-N’-nitro-N-nitrosoguanidine-induced genotoxicity and oxidative stress in mice. Drug Chem Toxicol 27:15–26PubMedCrossRefGoogle Scholar
  126. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446Google Scholar
  127. Taddei ML, Giannoni E, Raugei G, Scacco S, Sardanelli AM, Papa S, Chiarugi P (2012) Mitochondrial oxidative stress due to complex I dysfunction promotes fibroblast activation and melanoma cell invasiveness. Journal of Signal Transduction 2012Google Scholar
  128. Tait SW, Green DR (2012) Mitochondria and cell signalling. J Cell Sci 125:807–15PubMedCrossRefGoogle Scholar
  129. Tang L, Jin T, Zeng X, Wang J-S (2005) Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr 135:287–290PubMedGoogle Scholar
  130. Tang FY, Shih CJ, Cheng LH, Ho HJ, Chen HJ (2008) Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Molecular Nutr Food Res 52:646–654CrossRefGoogle Scholar
  131. Tanvetyanon T, Bepler G (2008) Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer 113:150–157PubMedCrossRefGoogle Scholar
  132. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029–1035CrossRefGoogle Scholar
  133. Tseng S-H, Lin S-M, Chen J-C, Su Y-H, Huang H-Y, Chen C-K, Lin P-Y, Chen Y (2004) Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res 10:2190–2202PubMedCrossRefGoogle Scholar
  134. Uppala PT, Dissmore T, Lau BH, Andacht T, Rajaram S (2012) Selective inhibition of cell proliferation by lycopene in MCF-7 breast cancer cells in vitro: a proteomic analysis. Phytother Res 27(4):595–601PubMedCrossRefGoogle Scholar
  135. Vardatsikos G, Sahu A, Srivastava AK (2009) The insulin-like growth factor family: molecular mechanisms, redox regulation, and clinical implications. Antioxid Redox Signal 11:1165–1190PubMedCrossRefGoogle Scholar
  136. Varis K, Taylor PR, Sipponen P, Samloff IM, Heinonen OP, Albanes D, Härkönen M, Huttunen JK, Laxen F, Virtamo J (1998) Gastric cancer and premalignant lesions in atrophic gastritis: a controlled trial on the effect of supplementation with alpha-tocopherol and beta-carotene. Scand J Gastroenterol 33:294–300PubMedCrossRefGoogle Scholar
  137. Veeraraghavan J, Aravindan S, Natarajanm M, Awasthi V, Herman TS, Aravindan N (2011a) Neem leaf extract induces radiosensitization in human neuroblastoma xenograft through modulation of apoptotic pathway. Anticancer Res 31:161–170Google Scholar
  138. Veeraraghavan J, Natarajan M, Lagisetty P, Awasthi V, Herman TS, Aravindan N (2011b) Impact of curcumin, raspberry extract, and neem leaf extract on rel protein-regulated cell death/radiosensitization in pancreatic cancer cells. Pancreas 40:1107–1119CrossRefGoogle Scholar
  139. Verhoeven D, Assen N, Goldbohm R, Dorant E, Van’T Veer P, Sturmans F, Hermus R, Van den Brandt P (1997) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer 75:149Google Scholar
  140. Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S (2010) The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. Eur J Pharmacol 649:84–91PubMedCrossRefGoogle Scholar
  141. Virtamo J, Pietinen P, Huttunen J, Korhonen P, Malila N, Virtanen M, Albanes D, Taylor P, Albert P (2003) Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 290:476–485PubMedCrossRefGoogle Scholar
  142. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–98PubMedCrossRefGoogle Scholar
  143. Wang X-D, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell RM (1999) Retinoid signaling and activator protein-1 expression in ferrets given β-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst 91:60–66PubMedCrossRefGoogle Scholar
  144. Wang Y, Zang QS, Liu Z, Wu Q, Maass D, Dulan G, Shaul PW, Melito L, Frantz DE, Kilgore JA (2011) Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol 301:C695–C704PubMedCrossRefGoogle Scholar
  145. Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  146. Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D (2009) Associations between α-tocopherol, β-carotene, and retinol and prostate cancer survival. Cancer Res 69:3833–3841PubMedCrossRefGoogle Scholar
  147. Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012) Autophagy: for better or for worse. Cell Res 22:43–61PubMedCrossRefGoogle Scholar
  148. Wu W, Chiang H, Fang J, Hung C (2007) Inhibitory effect of lycopene on PDGF-BB-induced signalling and migration in human dermal fibroblasts: a possible target for cancer. Biochem Soc Trans 35:1377–1378PubMedCrossRefGoogle Scholar
  149. Yasmineh W, Theologides A (1993) Catalase as a roving scavenger of hydrogen peroxide: A hypothesis. J Lab Clin Med 122:110–114PubMedGoogle Scholar
  150. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff D, Abel P, Tu Y (2013) Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32:4814–4824Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pharmacology and TherapeuticsRoswell Park Cancer InstituteBuffaloUSA

Personalised recommendations