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. 2009 Apr 16;14(3):497–510. doi: 10.2478/s11658-009-0016-2

Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines

Kyung Min Yang 1, Jong Ok Pyo 2, Gyu-Yeol Kim 3, Rina Yu 4, In Seob Han 5, Seong A Ju 6, Won Ho Kim 1, Byung-Sam Kim 5,✉
PMCID: PMC6275774  PMID: 19381455

Abstract

Although genetic factors are a well-known cause of colorectal cancer, environmental factors contribute more to its development. Despite advances in the fields of surgery, radiotherapy and chemotherapy, the cure rates for colon cancer have not substantially improved over the past few decades. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the principal pungent ingredient of hot chili pepper, has exhibited an anti-tumor effect in many cell types. However, the mechanisms responsible for the anti-tumor effect of capsaicin are not yet completely understood. In this study, we investigated whether capsaicin induces apoptosis in colon cancer cell lines. Capsaicin decreased cell viability in a dose-dependent manner in Colo320DM and LoVo cells. In addition, capsaicin produced cell morphology changes and DNA fragmentation, decreased the DNA contents, and induced phosphatidylserine translocation, which is a hallmark of apoptotic cell death. We showed that capsaicin-induced apoptosis is associated with an increase in ROS generation and a disruption of the mitochondrial transmenbrane potential. A possible mechanism of capsaicin-induced apoptosis is the activation of caspase 3, a major apoptosis-executing enzyme. Treatment with capsaicin induced a dramatic increase in caspase 3 activity, as assessed by the cleavage of Ac-DEVD-AMC, a fluorogenic substrate. In conclusion, our results clearly showed that capsaicin induced apoptosis in colon cancer cells. Although the actual mechanisms of capsaicin-induced apoptosis remain uncertain, it may be a beneficial agent for colon cancer treatment and chemoprevention.

Key words: Capsaicin, Colon cancer cell line, Apoptosis, Mitochondrial transmembrane potential, Reactive oxygen species, Caspase 3

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Abbreviations used

ΔΨm

mitochondrial transmembrane potential

MTT

13-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide

PI

propidium iodide

ROS

reactive oxygen species

References

  • 1.Hall P.A., Coates P.J., Ansari B., Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J. Cell Sci. 1994;107:3569–3577. doi: 10.1242/jcs.107.12.3569. [DOI] [PubMed] [Google Scholar]
  • 2.Bedi A., Pasricha P.J., Alchtar A.J., Barber J.P., Bedi G.C., Giairdiello F.M., Zahnbauer B.A., Hamitlton S.R., Jones R.J. Inhibition of apoptosis during development of colorectal cancer. Cancer Res. 1995;55:1811–1816. [PubMed] [Google Scholar]
  • 3.Cordell G.A., Araujo O.E. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann. Pharm. 1993;27:330–336. doi: 10.1177/106002809302700316. [DOI] [PubMed] [Google Scholar]
  • 4.Govindarajan V.S., Sathyanarayana M.N. Capsaicin-production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism: structure, pungent, pain, and desensitization sequences. CRC Crit. Rev. Food Sci. Nutr. 1991;29:435–474. doi: 10.1080/10408399109527536. [DOI] [PubMed] [Google Scholar]
  • 5.Dray A. Neuropharmacological mechanisms of capsaicin and related substances. Biochem. Pharmacol. 1992;44:611–615. doi: 10.1016/0006-2952(92)90393-W. [DOI] [PubMed] [Google Scholar]
  • 6.Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev. 1991;43:144–201. [PubMed] [Google Scholar]
  • 7.Szallasi A., Blumberg P. Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res. 1990;524:106–111. doi: 10.1016/0006-8993(90)90498-Z. [DOI] [PubMed] [Google Scholar]
  • 8.Szallasi A., Blumberg P. Vanilloid (capsaicin) receptor and mechanisms. Pharmacol Rev. 1999;51:159–211. [PubMed] [Google Scholar]
  • 9.Castillo-Olivares A., Yantiri F., Chueh P.J., Wang S., Sweeting M., Sedlak D., Morre D.M., Burgess J., Morre D.J. A drug-responsive and protease-resistant peripheral NADH oxidase complex from the surface of HeLa S cells. Arch. Biochem. Biophys. 1998;358:125–140. doi: 10.1006/abbi.1998.0823. [DOI] [PubMed] [Google Scholar]
  • 10.Ito K., Nakazato T., Murakami A., Yamato K., Miyakawa Y., Yamada T., Hozumi N., Ohigashi H., Ikeda Y., Kizaki M. Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res. 2004;64:1071–1078. doi: 10.1158/0008-5472.CAN-03-1670. [DOI] [PubMed] [Google Scholar]
  • 11.Kim J.D., Kim J.M., Pyo J.O., Kim S.Y., Kim B.S., Yu R., Han I.S. Capsaicin can alter the expression of tumor forming-related genes followed by induction of apoptosis of a Korean stomach cancer line, SNU-1. Cancer Lett. 1997;120:235–241. doi: 10.1016/S0304-3835(97)00321-2. [DOI] [PubMed] [Google Scholar]
  • 12.Kim C.S., Park W.H., Park J.Y., Kang J.H., Kim M.O., Kawada T., Yoo H., Han I.S., Yu R. Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the proliferator-activated receptor gamma in HT-29 human colon cancer cells. J. Med. Food. 2004;7:267–273. doi: 10.1089/jmf.2004.7.267. [DOI] [PubMed] [Google Scholar]
  • 13.Lee Y.S., Kang Y.S., Lee J.S., Nicolova S., Kim J.A. Involvement of NADPH oxidase-mediated generation of reactive oxygen species in the apoptotic cell death by capsaicin in HepG2 human hepatoma cells. Free Radic Res. 2004;38:405–412. doi: 10.1080/10715760410001665262. [DOI] [PubMed] [Google Scholar]
  • 14.Kim S., Moon A. Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation. Arch. Pharmacol. Res. 2004;27:845–849. doi: 10.1007/BF02980177. [DOI] [PubMed] [Google Scholar]
  • 15.Mori A., Lehmann S., O’Kelly J., Kumagai T., Desmond J.C., Pervan M., McBride W.H., Kizaki M., Koeffler H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006;66:3222–3229. doi: 10.1158/0008-5472.CAN-05-0087. [DOI] [PubMed] [Google Scholar]
  • 16.Vaux D.L., Korsmeyer S.J. Cell death in development. Cell. 1999;96:245–254. doi: 10.1016/S0092-8674(00)80564-4. [DOI] [PubMed] [Google Scholar]
  • 17.Mori A., Lehmann S., O’Kelly J., Kumagai T., Desmond J.C., Pervan M., McBride W.H., Kizaki M., Koeffler H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006;66:3222–3229. doi: 10.1158/0008-5472.CAN-05-0087. [DOI] [PubMed] [Google Scholar]
  • 18.Vermeulen K., Van Bockstaele D.R., Berneman Z.N. Apoptosis: mechanisms and relevance in cancer. Ann. Hematol. 2005;84:627–639. doi: 10.1007/s00277-005-1065-x. [DOI] [PubMed] [Google Scholar]
  • 19.Sánchez A.M., Sánchez M.G., Malagarie-Cazenave S., Olea N., Díaz-Laviada I. Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis. 2006;11:89–99. doi: 10.1007/s10495-005-3275-z. [DOI] [PubMed] [Google Scholar]
  • 20.Desagher S., Martinou J.C. Mitochondria as the central control point of apoptosis. Trends Cell Biol. 2000;10:369–377. doi: 10.1016/S0962-8924(00)01803-1. [DOI] [PubMed] [Google Scholar]
  • 21.Loeffler M., Kroemer G. The mitochondrion in cell death control: certainties and incognita. Exp. Cell Res. 2000;256:19–26. doi: 10.1006/excr.2000.4833. [DOI] [PubMed] [Google Scholar]
  • 22.Macho A., Calcado M.A., Munoz-Blanco J., Gomez-Diaz C., Gajate C., Mollinedo F., Navas P., Munoz E. Selective induction of apoptosis by capsaicin in transformed cells: The role of reactive oxygen species and calcium. Cell Death Differ. 1999;6:155–165. doi: 10.1038/sj.cdd.4400465. [DOI] [PubMed] [Google Scholar]
  • 23.Cohen G.M. Caspases: the executioners of apoptosis. Biochem. J. 1997;326:1–16. doi: 10.1042/bj3260001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Green D.R., Reed J.C. Mitochondria and apoptosis. Science. 1998;281:1309–1312. doi: 10.1126/science.281.5381.1309. [DOI] [PubMed] [Google Scholar]
  • 25.Jänicke R.U., Sprengart M.L., Wati M.R., Porter A.G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 1998;273:9357–9360. doi: 10.1074/jbc.273.16.9357. [DOI] [PubMed] [Google Scholar]
  • 26.Woo M., Hakem R., Soengas M.S., Duncan G.S., Shahinian A., Kägi D., Hakem A., McCurrach M., Khoo W., Kaufman S.A., Senaldi G., Howard T., Mak T.W. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 1998;12:806–819. doi: 10.1101/gad.12.6.806. [DOI] [PMC free article] [PubMed] [Google Scholar]

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