Role of Capsaicin in Prostate Cancer

Chapter
Part of the Diet and Cancer book series (DICA, volume 3)

Abstract

In the recent years, natural products have emerged as modulators of many cellular responses with potential applications as therapeutic drugs in many disorders. Among them, capsaicin, the pungent principle of chili peppers, has received an increasing attention for its strong chemo-preventive and chemotherapeutic ability in recent few years. In this chapter some of the molecular and cellular events initiated by treatment of prostate cancer cells with capsaicin are addressed and the potential role of capsaicin signaling network as target for prostate cancer treatment is discussed. Capsaicin induces cell cycle arrest and apoptosis in the androgen-insensitive prostate cancer PC-3 and DU-145 cell lines. Among the pathways underlying the mechanisms of action of capsaicin, ROS generation and ceramide accumulation seem to be the most relevant. In prostate PC-3 cells, capsaicin also induces endoplasmic reticulum stress and caspase-3 activation. Moreover, capsaicin exhibits anti-tumor growth activity in prostate tumors induced in mice. The data suggest that capsaicin holds promise as a treatment option for prostate cancer.

Keywords

Capsaicin Prostate cancer PC-3 cells LNCaP Apoptosis Tumor xenograft Ceramide 

References

  1. Andela VB, Gordon AH, Zotalis G et al (2003) Nfkappab: a pivotal transcription factor in prostate cancer metastasis to bone. Clin Orthop Relat Res 415 Suppl:S75–85PubMedCrossRefGoogle Scholar
  2. Athanasiou A, Smith PA, Vakilpour S et al (2007) Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: how vanilloids cause non-vanilloid receptor mediated cell death. Biochem Biophys Res Commun 354(1):50–55PubMedCrossRefGoogle Scholar
  3. Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50(Suppl):S91–96PubMedCrossRefGoogle Scholar
  4. Bartoletti R, Gavazzi A, Cai T et al (2009) Prostate growth and prevalence of prostate diseases in early onset spinal cord injuries. Eur Urol 56(1):142–148PubMedCrossRefGoogle Scholar
  5. Bidaux G, Roudbaraki M, Merle C et al (2005) Evidence for specific trpm8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement. Endocr Relat Cancer 12(2):367–382PubMedCrossRefGoogle Scholar
  6. Bieberich E (2004) Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: review and hypothesis. Glycoconj J 21(6):315–327PubMedCrossRefGoogle Scholar
  7. Bohlen CJ, Priel A, Zhou S, King D, Siemens J, Julius D (2010) A bivalent tarantula toxin activates the capsaicin receptor, trpv1, by targeting the outer pore domain. Cell 141(5):834–845PubMedCrossRefGoogle Scholar
  8. Brooks DD, Wolf A, Smith RA, Dash C, Guessous I (2010) Prostate cancer screening 2010: updated recommendations from the american cancer society. J Natl Med Assoc 102(5):423–429PubMedGoogle Scholar
  9. Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517PubMedCrossRefGoogle Scholar
  10. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824PubMedCrossRefGoogle Scholar
  11. Chow J, Norng M, Zhang J, Chai J (2007) Trpv6 mediates capsaicin-induced apoptosis in gastric cancer cells – mechanisms behind a possible new “Hot” cancer treatment. Biochim Biophys Acta 1773(4):565–576PubMedCrossRefGoogle Scholar
  12. Chuang YC, Yoshimura N, Wu M et al (2007) Intraprostatic capsaicin injection as a novel model for nonbacterial prostatitis and effects of botulinum toxin a. Eur Urol 51(4):1119–1127PubMedCrossRefGoogle Scholar
  13. Chuang YC, Yoshimura N, Huang CC, Wu M, Chiang PH, Chancellor MB (2008) Intraprostatic botulinum toxin a injection inhibits cyclooxygenase-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat. J Urol 180(2):742–748PubMedCrossRefGoogle Scholar
  14. Crane FL, Low H (2008) Reactive oxygen species generation at the plasma membrane for antibody control. Autoimmun Rev 7(7):518–522PubMedCrossRefGoogle Scholar
  15. Cui J, Bian JS, Kagan A, Mcdonald TV (2002) Cat1 contributes to the stores-operated calcium current in jurkat t-lymphocytes. J Biol Chem 277(49):47175–47183PubMedCrossRefGoogle Scholar
  16. Czifra G, Varga A, Nyeste K et al (2009) Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma. J Cancer Res Clin Oncol 135(4):507–514PubMedCrossRefGoogle Scholar
  17. De Luca T, Morre DM, Zhao H, Morre DJ (2005) Nad+/nadh and/or coq/coqh2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying g1 arrest and apoptosis. Biofactors 25(1–4):43–60PubMedCrossRefGoogle Scholar
  18. Dinis P, Charrua A, Avelino A et al (2005) The distribution of sensory fibers immunoreactive for the trpv1 (capsaicin) receptor in the human prostate. Eur Urol 48(1):162–167PubMedCrossRefGoogle Scholar
  19. Fernandez-Ballester G, Ferrer-Montiel A (2008) Molecular modeling of the full-length human trpv1 channel in closed and desensitized states. J Membr Biol 223(3):161–172PubMedCrossRefGoogle Scholar
  20. Ferrer-Montiel A, Garcia-Martinez C, Morenilla-Palao C et al (2004) Molecular architecture of the vanilloid receptor. Insights for drug design. Eur J Biochem 271(10):1820–1826PubMedCrossRefGoogle Scholar
  21. Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H (2003) Expression of the ca2+-selective cation channel trpv6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene 22(49):7858–7861PubMedCrossRefGoogle Scholar
  22. Fizazi K, Sternberg CN, Fitzpatrick JM, Watson RW, Tabesh M (2010) Role of targeted therapy in the treatment of advanced prostate cancer. BJU Int 105(6):748–767PubMedCrossRefGoogle Scholar
  23. Garcia-Cao I, Duran A, Collado M et al (2005) Tumour-suppression activity of the proapoptotic regulator par4. EMBO Rep 6(6):577–583PubMedCrossRefGoogle Scholar
  24. Gratzke C, Weinhold P, Reich O et al (2010) Transient receptor potential a1 and cannabinoid receptor activity in human normal and hyperplastic prostate: relation to nerves and interstitial cells. Eur Urol 57(5):902–910PubMedCrossRefGoogle Scholar
  25. Hail N Jr (2003) Mechanisms of vanilloid-induced apoptosis. Apoptosis 8(3):251–262PubMedCrossRefGoogle Scholar
  26. Henshall SM, Afar DE, Hiller J et al (2003) Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse. Cancer Res 63(14):4196–4203PubMedGoogle Scholar
  27. Horoszewicz JS, Leong SS, Kawinski E et al (1983) Lncap model of human prostatic carcinoma. Cancer Res 43(4):1809–1818PubMedGoogle Scholar
  28. Iype PT, Iype LE, Verma M, Kaighn ME (1998) Establishment and characterization of immortalized human cell lines from prostatic carcinoma and benign prostatic hyperplasia. Int J Oncol 12(2):257–263PubMedGoogle Scholar
  29. Jankovic B, Loblaw DA, Nam R (2010) Capsaicin may slow psa doubling time: case report and literature review. Can Urol Assoc J 4(1):E9–E11PubMedGoogle Scholar
  30. Jiang Z, Gorenstein NM, Morre DM, Morre DJ (2008) Molecular cloning and characterization of a candidate human growth-related and time-keeping constitutive cell surface hydroquinone (nadh) oxidase. Biochemistry 47(52):14028–14038PubMedCrossRefGoogle Scholar
  31. Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97(14):8134–8139PubMedCrossRefGoogle Scholar
  32. Jung J, Hwang SW, Kwak J et al (1999) Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. J Neurosci 19(2):529–538PubMedGoogle Scholar
  33. Kuramori C, Azuma M, Kume K et al (2009) Capsaicin binds to prohibitin 2 and displaces it from the mitochondria to the nucleus. Biochem Biophys Res Commun 379(2):519–525PubMedCrossRefGoogle Scholar
  34. Lallet-Daher H, Roudbaraki M, Bavencoffe A et al (2009) Intermediate-conductance ca2+-activated k+ channels (ikca1) regulate human prostate cancer cell proliferation through a close control of calcium entry. Oncogene 28(15):1792–1806PubMedCrossRefGoogle Scholar
  35. Lehen’kyi V, Flourakis M, Skryma R, Prevarskaya N (2007) Trpv6 channel controls prostate cancer cell proliferation via ca(2+)/nfat-dependent pathways. Oncogene 26(52):7380–7385PubMedCrossRefGoogle Scholar
  36. Lishko PV, Procko E, Jin X, Phelps CB, Gaudet R (2007) The ankyrin repeats of trpv1 bind multiple ligands and modulate channel sensitivity. Neuron 54(6):905–918PubMedCrossRefGoogle Scholar
  37. Liu X, Cheng JC, Turner LS et al (2009) Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy. Expert Opin Ther Targets 13(12):1449–1458PubMedCrossRefGoogle Scholar
  38. Macho A, Calzado MA, Munoz-Blanco J et al (1999) Selective induction of apoptosis by capsaicin in transformed cells: the role of reactive oxygen species and calcium. Cell Death Differ 6(2):155–165PubMedCrossRefGoogle Scholar
  39. Macho A, Sancho R, Minassi A, Appendino G, Lawen A, Munoz E (2003) Involvement of reactive oxygen species in capsaicinoid-induced apoptosis in transformed cells. Free Radic Res 37(6):611–619PubMedCrossRefGoogle Scholar
  40. Malagarie-Cazenave S, Olea-Herrero N, Vara D, Diaz-Laviada I (2009) Capsaicin, a component of red peppers, induces expression of androgen receptor via pi3k and mapk pathways in prostate lncap cells. FEBS Lett 583(1):141–147PubMedCrossRefGoogle Scholar
  41. Messeguer A, Planells-Cases R, Ferrer-Montiel A (2006) Physiology and pharmacology of the vanilloid receptor. Curr Neuropharmacol 4(1):1–15PubMedCrossRefGoogle Scholar
  42. Monet M, Lehen’kyi V, Gackiere F et al (2010) Role of cationic channel trpv2 in promoting prostate cancer migration and progression to androgen resistance. Cancer Res 70(3):1225–1235PubMedCrossRefGoogle Scholar
  43. Montell C, Birnbaumer L, Flockerzi V (2002) The trp channels, a remarkably functional family. Cell 108(5):595–598PubMedCrossRefGoogle Scholar
  44. Mori A, Lehmann S, O’kelly J et al (2006) Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res 66(6):3222–3229PubMedCrossRefGoogle Scholar
  45. Morre DJ, Morre DM (2006) Aging-related cell surface ecto-nox protein, arnox, a preventive target to reduce atherogenic risk in the elderly. Rejuvenation Res 9(2):231–236PubMedCrossRefGoogle Scholar
  46. Morre DJ, Chueh PJ, Morre DM (1995) Capsaicin inhibits preferentially the nadh oxidase and growth of transformed cells in culture. Proc Natl Acad Sci USA 92(6):1831–1835PubMedCrossRefGoogle Scholar
  47. Morre DJ, Sun E, Geilen C et al (1996) Capsaicin inhibits plasma membrane nadh oxidase and growth of human and mouse melanoma lines. Eur J Cancer 32A(11):1995–2003PubMedCrossRefGoogle Scholar
  48. Morre DJ, Caldwell S, Mayorga A, Wu LY, Morre DM (1997) Nadh oxidase activity from sera altered by capsaicin is widely distributed among cancer patients. Arch Biochem Biophys 342(2):224–230PubMedCrossRefGoogle Scholar
  49. Morre DJ, Morre DM, Shelton TB (2010) Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the french paradox revisited. Rejuvenation Res 13(2–3):159–161PubMedCrossRefGoogle Scholar
  50. Ozbayraktar FB, Ulgen KO (2009) Molecular facets of sphingolipids: mediators of diseases. Biotechnol J 4(7):1028–1041PubMedCrossRefGoogle Scholar
  51. Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD (1999) Constitutive activation of ikappab kinase alpha and nf-kappab in prostate cancer cells is inhibited by ibuprofen. Oncogene 18(51):7389–7394PubMedCrossRefGoogle Scholar
  52. Peng JB, Zhuang L, Berger UV et al (2001) Cat1 Expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun 282(3):729–734PubMedCrossRefGoogle Scholar
  53. Phelps CB, Procko E, Lishko PV, Wang RR, Gaudet R (2007) Insights into the roles of conserved and divergent residues in the ankyrin repeats of trpv ion channels. Channels (Austin) 1(3):148–151Google Scholar
  54. Prevarskaya N, Zhang L, Barritt G (2007) Trp channels in cancer. Biochim Biophys Acta 1772(8):937–946PubMedCrossRefGoogle Scholar
  55. Rho YW, Bae YS (2010) Capsaicin, a component of red peppers, stimulates protein kinase ckii activity. BMB Rep 43(5):325–329PubMedCrossRefGoogle Scholar
  56. Sanchez MG, Sanchez AM, Collado B et al (2005) Expression of the transient receptor potential vanilloid 1 (trpv1) in lncap and pc-3 prostate cancer cells and in human prostate tissue. Eur J Pharmacol 515(1–3):20–27PubMedCrossRefGoogle Scholar
  57. Sanchez AM, Sanchez MG, Malagarie-Cazenave S, Olea N, Diaz-Laviada I (2006) Induction of apoptosis in prostate tumor pc-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis 11(1):89–99PubMedCrossRefGoogle Scholar
  58. Sanchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chiloeches A, Diaz-Laviada I (2007) Apoptosis induced by capsaicin in prostate pc-3 cells involves ceramide accumulation, neutral sphingomyelinase, and jnk activation. Apoptosis 12(11):2013–2024PubMedCrossRefGoogle Scholar
  59. Sanchez AM, Martinez-Botas J, Malagarie-Cazenave S et al (2008) Induction of the endoplasmic reticulum stress protein gadd153/chop by capsaicin in prostate pc-3 cells: a microarray study. Biochem Biophys Res Commun 372(4):785–791PubMedCrossRefGoogle Scholar
  60. Sells SF, Wood DP Jr, Joshi-Barve SS et al (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ 5(4):457–466PubMedGoogle Scholar
  61. Sells SF, Han S, Muthukkumar S et al (1997) Expression and function of the leucine zipper protein par-4 in apoptosis. Mol Cell Biol 17(7):3823–3832PubMedGoogle Scholar
  62. Sikka SC, Huang L et al (2010) Novel role for the transient receptor potential channel trpm2 in prostate cancer cell proliferation. Prostate Cancer Prostatic Dis 13(2):195–201PubMedCrossRefGoogle Scholar
  63. Stavridi F, Karapanagiotou EM, Syrigos KN (2010) Targeted therapeutic approaches for hormone-refractory prostate cancer. Cancer Treat Rev 36(2):122–130PubMedCrossRefGoogle Scholar
  64. Stone KR, Mickey DD, Wunderli H, Mickey GH, Paulson DF (1978) Isolation of a human prostate carcinoma cell line (du 145). Int J Cancer 21(3):274–281PubMedCrossRefGoogle Scholar
  65. Szallasi A (2001) Vanilloid receptor ligands: hopes and realities for the future. Drugs Aging 18(8):561–573PubMedCrossRefGoogle Scholar
  66. Tsavaler L, Shapero MH, Morkowski S, Laus R (2001) Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res 61(9):3760–3769PubMedGoogle Scholar
  67. Ursu D, Knopp K, Beattie RE, Liu B, Sher E (2010) Pungency of trpv1 agonists is directly correlated with kinetics of receptor activation and lipophilicity. Eur J Pharmacol 641(2–3):114–122PubMedCrossRefGoogle Scholar
  68. Van Der Aa F, Roskams T, Blyweert W, De Ridder D (2003) Interstitial cells in the human prostate: a new therapeutic target? Prostate 56(4):250–255PubMedCrossRefGoogle Scholar
  69. Vriens J, Appendino G, Nilius B (2009) Pharmacology of vanilloid transient receptor potential cation channels. Mol Pharmacol 75(6):1262–1279PubMedCrossRefGoogle Scholar
  70. Walpole CS, Wrigglesworth R, Bevan S et al (1993) Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain “C-region”. J Med Chem 36(16):2381–2389PubMedCrossRefGoogle Scholar
  71. Walpole CS, Bevan S, Bloomfield G et al (1996) Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues. J Med Chem 39(15):2939–2952PubMedCrossRefGoogle Scholar
  72. Wang HP, Pu XY, Wang XH (2007) Distribution profiles of transient receptor potential melastatin-related and vanilloid-related channels in prostatic tissue in rat. Asian J Androl 9(5):634–640PubMedCrossRefGoogle Scholar
  73. Wang G, Yang ZQ, Zhang K (2010) Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Am J Transl Res 2(1):65–74PubMedGoogle Scholar
  74. Webber MM, Bello D, Quader S (1997) Immortalized and tumorigenic adult human prostatic epithelial cell lines: characteristics and applications part 2. Tumorigenic cell lines. Prostate 30(1):58–64PubMedCrossRefGoogle Scholar
  75. Wissenbach U, Niemeyer BA (2007) Trpv6. Handb Exp Pharmacol 179:221–234PubMedCrossRefGoogle Scholar
  76. Wissenbach U, Niemeyer BA, Fixemer T et al (2001) Expression of cat-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem 276(22):19461–19468PubMedCrossRefGoogle Scholar
  77. Wissenbach U, Niemeyer B, Himmerkus N, Fixemer T, Bonkhoff H, Flockerzi V (2004) Trpv6 And prostate cancer: cancer growth beyond the prostate correlates with increased trpv6 ca2+ channel expression. Biochem Biophys Res Commun 322(4):1359–1363PubMedCrossRefGoogle Scholar
  78. Yang ZH, Wang XH, Wang HP, Hu LQ (2009) Effects of trpm8 on the proliferation and motility of prostate cancer pc-3 cells. Asian J Androl 11(2):157–165PubMedCrossRefGoogle Scholar
  79. Zhang L, Barritt GJ (2004) Evidence that trpm8 is an androgen-dependent ca2+ channel required for the survival of prostate cancer cells. Cancer Res 64(22):8365–8373PubMedCrossRefGoogle Scholar
  80. Zhang L, Barritt GJ (2006) Trpm8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function? Endocr Relat Cancer 13(1):27–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology, School of MedicineUniversity of AlcaláMadridSpain

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