A Perspective on Chemoprevention by Resveratrol in Head and Neck Squamous Cell Carcinoma

  • Sangeeta Shrotriya
  • Rajesh Agarwal
  • Robert A. SclafaniEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 815)


Head and neck squamous cell carcinoma (HNSCC) accounts for around 6 % of all cancers in the USA. Few of the greatest obstacles in HNSCC include development of secondary primary tumor, resistance and toxicity associated with the conventional treatments, together decreasing the overall 5-year survival rate in HNSCC patients to ≤50 %. Radiation and chemotherapy are the conventional treatment options available for HNSCC patients at both early and late stage of this cancer type malignancy. Unfortunately, patients response poorly to these therapies leading to relapsed cases, which further, emphasizes the need of additional strategies for the prevention/intervention of both primary and the secondary primary tumors post-HNSCC therapy. In recent years, growing interest has focused on the use of natural products or their analogs to reduce the incidence and mortality of cancer, leading to encouraging results. Resveratrol, a component from grape skin, is one of the well-studied agents with a potential role in cancer chemoprevention and other health benefits. As an anticancer agent, resveratrol suppresses metabolic activation of pro-carcinogens to carcinogens by modulating the metabolic enzymes responsible for their activation, and induces phase II enzymes, thus, further detoxifying the effect of pro-carcinogens. Resveratrol also inhibits cell growth and induces cell death in cancer cells by targeting cell survival and cell death regulatory pathways. Growing evidence also suggest that resveratrol directly binds to DNA and RNA, activates antioxidant enzymes, prevents inflammation, and stimulates DNA damage checkpoint kinases affecting genomic integrity more specifically in malignant cells.


Human Papilloma Virus Fanconi Anemia Ataxia Telangiectasia Mutate Apoptosis Ligand Alcohol Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



4-Nitroquinoline 1-oxide


Alcohol dehydrogenase


Aldehyde dehydrogenase


Activator protein 1


Antioxidant response element


Ataxia telangiectasia mutated


Ataxia telangiectasia-Rad3-related




Base excision repair


Breast cancer gene 1


Cell division cycle 25C


Cyclin dependent kinases


Checkpoint kinase 1/2


Cyclooxygenase 2


Cytochrome P450s




Double strand break


Epidermal growth factor receptor

Egr 1

Early growth response 1


Epithelial mesenchymal transition


Fanconi anemia




Head and neck squamous cell carcinoma


Human papilloma virus


Homologous recombination repair


Insulin-like growth factor receptor


Inducible nitric oxide synthetase


c-Jun N-terminal kinase


Mitogen-activated protein kinases


Minichromosome maintenance




Mismatch repair


Mammalian target of rapamycin


Nucleotide excision repair


Nuclear factor kappa B


Non-homologous end joining




Protein 53


Poly (ADP-ribose) polymerases


Proliferating cell nuclear antigen


Retinoic acid


Retinoblastoma protein




Reactive oxygen species/reactive nitrogen species


Secondary primary tumor


Single strand break


Signal transducer and activator of transcription 3


Grant Support:

Supported by grants to R. Sclafani from the Fanconi Anemia Research Foundation and the University of Colorado Cancer Center.


  1. 1.
    Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71(10):1397–1421PubMedCrossRefGoogle Scholar
  2. 2.
    Balbo S, Meng L et al (2012) Kinetics of DNA adduct formation in the oral cavity after drinking alcohol. Cancer Epidemiol Biomarkers Prev 21(4):601–608PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Basso E, Fiore M et al (2013) Effects of resveratrol on topoisomerase II-alpha activity: induction of micronuclei and inhibition of chromosome segregation in CHO-K1 cells. Mutagenesis 28(3):243–248PubMedCrossRefGoogle Scholar
  4. 4.
    Bo S, Ciccone G et al (2013) Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem 20(10):1323–1331PubMedCrossRefGoogle Scholar
  5. 5.
    Brown GC, Borutaite V (2011) There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells. Mitochondrion 12(1):1–4PubMedCrossRefGoogle Scholar
  6. 6.
    Buonocore D, Lazzeretti A et al (2012) Resveratrol-procyanidin blend: nutraceutical and antiaging efficacy evaluated in a placebocontrolled, double-blind study. Clin Cosmet Investig Dermatol 5:159–165PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Choi S, Myers JN (2008) Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 87(1):14–32PubMedCrossRefGoogle Scholar
  8. 8.
    Connell PP, Jayathilaka K et al (2006) Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers. Int J Oncol 28(5):1113–1119PubMedGoogle Scholar
  9. 9.
    Cui R, Kamatani Y et al (2009) Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 137(5):1768–1775PubMedCrossRefGoogle Scholar
  10. 10.
    Day GL, Blot WJ et al (1994) Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86(2):131–137PubMedCrossRefGoogle Scholar
  11. 11.
    De Groote D, Van Belleghem K et al (2012) Effect of the intake of resveratrol, resveratrol phosphate, and catechin-rich grape seed extract on markers of oxidative stress and gene expression in adult obese subjects. Ann Nutr Metab 61(1):15–24PubMedCrossRefGoogle Scholar
  12. 12.
    Derry MM, Raina K et al (2013) Identifying molecular targets of lifestyle modifications in colon cancer prevention. Front Oncol 3:119PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Dudek AZ, Lesniewski-Kmak K et al (2009) Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer 100(9):1379–1384PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Ferlay J, Shin HR et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917PubMedCrossRefGoogle Scholar
  15. 15.
    Fortune JM, Osheroff N (2000) Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog Nucleic Acid Res Mol Biol 64:221–253PubMedCrossRefGoogle Scholar
  16. 16.
    Fouret P, Monceaux G et al (1997) Human papillomavirus in head and neck squamous cell carcinomas in nonsmokers. Arch Otolaryngol Head Neck Surg 123(5):513–516PubMedCrossRefGoogle Scholar
  17. 17.
    Freedman ND, Schatzkin A et al (2007) Alcohol and head and neck cancer risk in a prospective study. Br J Cancer 96(9):1469–1474PubMedCentralPubMedGoogle Scholar
  18. 18.
    Freudlsperger C, Burnett JR et al (2010) EGFR-PI3K-AKT-mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy. Expert Opin Ther Targets 15(1):63–74PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Furgason JM, Bahassi M et al (2012) Targeting DNA repair mechanisms in cancer. Pharmacol Ther 137(3):298–308PubMedCrossRefGoogle Scholar
  20. 20.
    Garaycoechea JI, Crossan GP et al (2012) Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489(7417):571–575PubMedCrossRefGoogle Scholar
  21. 21.
    Gatz SA, Wiesmuller L (2008) Take a break—resveratrol in action on DNA. Carcinogenesis 29(2):321–332PubMedCrossRefGoogle Scholar
  22. 22.
    Gillison ML, Koch WM et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92(9):709–720PubMedCrossRefGoogle Scholar
  23. 23.
    Hira A, Yabe H et al (2013) Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. Blood 122(18):3206–3209PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411(6835):366–374PubMedCrossRefGoogle Scholar
  25. 25.
    Hong WK, Endicott J et al (1986) 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315(24):1501–1505PubMedCrossRefGoogle Scholar
  26. 26.
    Howard JD, Lu B et al (2012) Therapeutic targets in head and neck squamous cell carcinoma: identification, evaluation, and clinical translation. Oral Oncol 48(1):10–17PubMedCrossRefGoogle Scholar
  27. 27.
    Howells LM, Berry DP et al (2011) Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases–safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila) 4(9):1419–1425CrossRefGoogle Scholar
  28. 28.
    Irish JC, Bernstein A (1993) Oncogenes in head and neck cancer. Laryngoscope 103(1 Pt 1):42–52PubMedGoogle Scholar
  29. 29.
    Ishiji T (2000) Molecular mechanism of carcinogenesis by human papillomavirus-16. J Dermatol 27(2):73–86PubMedGoogle Scholar
  30. 30.
    Jelski W, Kutylowska E et al (2011) Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as candidates for tumor markers in patients with pancreatic cancer. J Gastrointestin Liver Dis 20(3):255–259PubMedGoogle Scholar
  31. 31.
    Kundu SK, Nestor M (2012) Targeted therapy in head and neck cancer. Tumour Biol 33(3):707–721PubMedCrossRefGoogle Scholar
  32. 32.
    Lachenmeier DW, Monakhova YB (2011) Short-term salivary acetaldehyde increase due to direct exposure to alcoholic beverages as an additional cancer risk factor beyond ethanol metabolism. J Exp Clin Cancer Res 30:3PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Lanzilli G, Fuggetta MP et al (2006) Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. Int J Oncol 28(3):641–648PubMedGoogle Scholar
  34. 34.
    Leemans CR, Braakhuis BJ et al (2011) The molecular biology of head and neck cancer. Nat Rev Cancer 11(1):9–22PubMedCrossRefGoogle Scholar
  35. 35.
    Lenaz G (2001) The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 52(3–5):159–164PubMedCrossRefGoogle Scholar
  36. 36.
    Leon-Galicia I, Diaz-Chavez J et al (2013) Resveratrol induces downregulation of DNA repair genes in MCF-7 human breast cancer cells. Eur J Cancer Prev 22(1):11–20PubMedCrossRefGoogle Scholar
  37. 37.
    Maacke H, Opitz S et al (2000) Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. Int J Cancer 88(6):907–913PubMedCrossRefGoogle Scholar
  38. 38.
    Maiorano D, Lutzmann M et al (2006) MCM proteins and DNA replication. Curr Opin Cell Biol 18(2):130–136PubMedCrossRefGoogle Scholar
  39. 39.
    Markus MA, Marques FZ et al (2011) Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs. PLoS One 6(12):e28926PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Martins LA, Coelho BP et al (2014) Resveratrol induces pro-oxidant effects and time-dependent resistance to cytotoxicity in activated hepatic stellate cells. Cell Biochem Biophys 68(2):247–257PubMedCrossRefGoogle Scholar
  41. 41.
    Mitra A, Jameson C et al (2009) Overexpression of RAD51 occurs in aggressive prostatic cancer. Histopathology 55(6):696–704PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Nassiri-Asl M, Hosseinzadeh H (2009) Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother Res 23(9):1197–1204PubMedCrossRefGoogle Scholar
  43. 43.
    Nguyen SA, Walker D et al (2012) mTOR inhibitors and its role in the treatment of head and neck squamous cell carcinoma. Curr Treat Options Oncol 13(1):71–81PubMedCrossRefGoogle Scholar
  44. 44.
    O’Neil N, Rose A (2006) DNA repair. WormBook, pp 1–12Google Scholar
  45. 45.
    Ohba S, Fujii H et al (2009) Overexpression of GLUT-1 in the invasion front is associated with depth of oral squamous cell carcinoma and prognosis. J Oral Pathol Med 39(1):74–78PubMedCrossRefGoogle Scholar
  46. 46.
    Paglin S, Hollister T et al (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61(2):439–444PubMedGoogle Scholar
  47. 47.
    Pavlov YI, Shcherbakova PV et al (2006) Roles of DNA polymerases in replication, repair, and recombination in eukaryotes. Int Rev Cytol 255:41–132PubMedCrossRefGoogle Scholar
  48. 48.
    Petti S (2009) Lifestyle risk factors for oral cancer. Oral Oncol 45(4–5):340–350PubMedCrossRefGoogle Scholar
  49. 49.
    Poeta ML, Manola J et al (2007) TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 357(25):2552–2561PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Radhakrishnan S, Reddivari L et al (2011) Resveratrol potentiates grape seed extract induced human colon cancer cell apoptosis. Front Biosci (Elite Ed) 3:1509–1523Google Scholar
  51. 51.
    Radojicic J, Zaravinos A et al (2012) HPV, KRAS mutations, alcohol consumption and tobacco smoking effects on esophageal squamous-cell carcinoma carcinogenesis. Int J Biol Markers 27(1):1–12PubMedCrossRefGoogle Scholar
  52. 52.
    Rakoff-Nahoum S (2006) Why cancer and inflammation? Yale J Biol Med 79(3–4):123–130PubMedCentralPubMedGoogle Scholar
  53. 53.
    Roy S, Kaur M et al (2007) p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells. Mol Cancer Ther 6(10):2696–2707PubMedCrossRefGoogle Scholar
  54. 54.
    Rusin P, Olszewski J et al (2009) Comparative study of DNA damage and repair in head and neck cancer after radiation treatment. Cell Biol Int 33(3):357–363PubMedCrossRefGoogle Scholar
  55. 55.
    Sanchez-Alvarez R, Martinez-Outschoorn UE et al (2013) Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention. Cell Cycle 12(2):289–301PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Sankaranarayanan R, Masuyer E et al (1998) Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res 18(6B):4779–4786PubMedGoogle Scholar
  57. 57.
    Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7(8):599–612PubMedCrossRefGoogle Scholar
  58. 58.
    Sharafinski ME, Ferris RL et al (2010) Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 32(10):1412–1421PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Siegel R, Naishadham D et al (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30PubMedCrossRefGoogle Scholar
  60. 60.
    Signorelli P, Ghidoni R (2005) Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16(8):449–466PubMedCrossRefGoogle Scholar
  61. 61.
    Smith J, Tho LM et al (2010) The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 108:73–112PubMedCrossRefGoogle Scholar
  62. 62.
    Tome-Carneiro J, Larrosa M et al (2013) Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 19(34):6064–6093PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Trachootham D, Alexandre J et al (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591PubMedCrossRefGoogle Scholar
  64. 64.
    Tsao AS, Garden AS et al (2006) Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck. J Clin Oncol 24(25):4163–4169PubMedCrossRefGoogle Scholar
  65. 65.
    Turati F, Garavello W et al (2010) A meta-analysis of alcohol drinking and oral and pharyngeal cancers. Part 2: results by subsites. Oral Oncol 46(10):720–726PubMedCrossRefGoogle Scholar
  66. 66.
    Tyagi A, Gu M et al (2011) Resveratrol selectively induces DNA damage, independent of Smad4 expression, in its efficacy against human head and neck squamous cell carcinoma. Clin Cancer Res 17(16):5402–5411PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Tyagi A, Singh RP et al (2005) Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells. Carcinogenesis 26(11):1978–1987PubMedCrossRefGoogle Scholar
  68. 68.
    Wang M, Chu H et al (2013) Molecular epidemiology of DNA repair gene polymorphisms and head and neck cancer. J Biomed Res 27(3):179–192PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Weng CJ, Yen GC (2012) Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives. Cancer Treat Rev 38(1):76–87PubMedCrossRefGoogle Scholar
  70. 70.
    Woutersen RA, Appelman LM et al (1986) Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 41(2):213–231PubMedCrossRefGoogle Scholar
  71. 71.
    Yokoyama A, Muramatsu T et al (1998) Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Carcinogenesis 19(8):1383–1387PubMedCrossRefGoogle Scholar
  72. 72.
    Chow, H. H., L. L. Garland, et al. (2010). “Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study.” Cancer Prev Res (Phila) 3(9): 1168–1175CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Sangeeta Shrotriya
    • 1
  • Rajesh Agarwal
    • 1
    • 2
  • Robert A. Sclafani
    • 2
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity of Colorado DenverAuroraUSA
  2. 2.University of Colorado Cancer Center, University of Colorado DenverAuroraUSA
  3. 3.Department of Biochemistry and Molecular GeneticsUniversity of Colorado DenverAuroraUSA

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