Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Anticarcinogenic Effect of S-allylcysteine (SAC)

S-allylcysteine의 항암효과

  • Kong, Il-Keun (Department of Animal Science, Division of Applied Life Science (BK21 plus), Gyeongsang National University) ;
  • Kim, Hyun Hee (Department of Animal Science, Division of Applied Life Science (BK21 plus), Gyeongsang National University) ;
  • Min, Gyesik (Department of Nursing, College of Life Science, Gyeongnam National University of Science & Technology)
  • 공일근 (경상대학교 응용생명과학부) ;
  • 김현희 (경상대학교 응용생명과학부) ;
  • 민계식 (경남과학기술대학교 생명과학대학 간호학과)
  • Received : 2015.11.18
  • Accepted : 2015.11.25
  • Published : 2015.11.30
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Abstract

S-allylcysteine (SAC) is an aged garlic derived water soluble organosulfur compound and has been suggested to have anticarcinogenic activity against diverse types of cancer cells. This review summarizes the cellular signaling pathways and molecular mechanisms whereby SAC exerts its effects on cellular proliferation, apoptosis, cell cycle progression and metastasis based on the results from both in vitro and in vivo studies. SAC activates proapoptotic proteins including Bax and caspase-3, but suppresses antiapoptotic Bcl-2 family proteins to bring about cancer cell death through mitochondria-mediated intrinsic pathway. SAC also inhibits cellular proliferation by inducing cell cycle arrest in which SAC reduces expression and activation of NF-κB, cyclins, Cdks, PCNA and c-Jun, but elevates expression of cell cycle inhibitor proteins p16 and p21 through suppression of both PI3K/Akt/mTOR and MAPK/ERK signaling pathways. And, SAC inhibits invasion and metastasis of cancer cells by inducing suppression of both angiogenesis and epithelial-mesenchymal transition (EMT) through decreased cyclooxygenase (COX)-2 expression and increased E-cadherin expression which were then caused by suppression of inhibitory transcription factors Id-1 and SLUG from SAC-mediated inactivation of both MAPK/ERK and PI3K/Akt/mTOR/NF-κB signaling pathways. Furthermore, SAC prevents toxic compound-induced carcinogenesis by inducing antioxidant enzymes such as glutathione-s-transferase (GST). Thus, SAC can be considered as a potential chemotherapeutic agent for the prevention and treatment of cancer.

S-allylcysteine (SAC)은 숙성된 마늘로부터 유래된 수용성 유기황화합물로서, 여러 유형의 암세포에 대한 항암효과를 갖는 것으로 제시되어왔다. 본 논문은 in vitro 및 in vivo 연구결과에 기초하여 SAC가 세포증식, 세포사멸, 세포주기 및 전이에 미치는 세포신호전달경로와 분자적 메커니즘을 정리하였다. SAC는 Bax와 caspase-3을 포함하는 세포사멸촉진 단백질을 활성화하고 Bcl-2 세포사멸억제 단백질군을 억제하여 미토콘드리아-매개 내인성 경로를 통한 세포사멸을 초래 한다. SAC는 또한 PI3K/Akt/mTOR 및 MAPK/ERK 신호전달경로를 억제하여 NF-κB, cyclins, Cdks, PCNA 및 c-Jun의 발현과 활성을 감소시키고, 세포주기 억제단백질인 p16 및 p21의 발현을 증가시킴으로써 세포주기 억제를 유도하여 세포증식을 억제한다. 뿐만 아니라, SAC는 glutathione-s-transferase (GST)와 같은 항산화효소의 활성을 유도하여 독성물질에 의해 유도된 발암작용을 방지한다. 그리고, SAC는 MAPK/ERK 및 PI3K/Akt/mTOR/NF-κB 신호경로의 억제를 통한 전사억제조절인자 Id-1 및 SLUG의 발현억제를 통하여 초래된 COX-2의 발현감소와 E-cadherin의 발현증가에 의해 신생혈관생성과 MET의 억제를 유도함으로써 암세포의 침투와 전이를 억제한다. 따라서, SAC는 암의 예방과 치료를 위한 하나의 잠재적 화학요법제로 간주될 수 있다.

Keywords

References

  1. Amagase, H. and Milner, J. A. 1993. Impact of various sources of garlic and their constituents on 7,12-dimethylbenz[a] anthracene binding to mammary cell DNA. Carcinogenesis 14, 1627-1631. https://doi.org/10.1093/carcin/14.8.1627
  2. Balasenthil, S., Rao, K. S. and Nagini, S. 2002. Apoptosis induction by S-allylcysteine, a garlic constituent, during 7, 12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Cell Biochem. Funct. 20, 263-268. https://doi.org/10.1002/cbf.967
  3. Bhatia, K., Ahmad, F., Rashid, H. and Raisuddin, S. 2008. Protective effect of S-allylcysteine against cyclophosphamideinduced bladder hemorrhagic cystitis in mice. Food Chem. Toxicol. 46, 3368-3374. https://doi.org/10.1016/j.fct.2008.08.011
  4. Birchmeier, W. and Behrens, J. 1994. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta. 1198, 11-26.
  5. Bracke, M. E., Van, Roy. F. M. and Mareel, M. M. 1996. The E-cadherin/catenin complex in invasion and metastasis. Curr. Top Microbiol. Immunol. 213, 123-161.
  6. Butt, M. S., Sultan, M. T., Butt, M. S. and Iqbal, J. 2009. Garlic: nature’s protection against physiological threats. Crit. Rev. Food Sci. Nutr. 49, 538-551. https://doi.org/10.1080/10408390802145344
  7. Cerutti, P. A. 1985. Prooxidant states and tumor promotion. Science 227, 375-381. https://doi.org/10.1126/science.2981433
  8. Chu, Q., Lee, D. T., Tsao, S. W., Wang, X. and Wong, Y. C. 2007. S-allylcysteine, a water-soluble garlic derivative, suppresses the growth of a human androgen-independent prostate cancer xenograft, CWR22R, under in vivo conditions. BJU Int. 99, 925-932. https://doi.org/10.1111/j.1464-410X.2006.06639.x
  9. Chu, Q., Ling, M. T., Feng, H., Cheung, H. W., Tsao, S. W., Wang, X. and Wong, Y. C. 2006. A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression. Carcinogenesis 27, 2180-2189. https://doi.org/10.1093/carcin/bgl054
  10. Cohen, L. A., Zhao, Z., Pittman, B. and Lubet, R. 1999. S-allylcysteine, a garlic constituent, fails to inhibit N-methylnitrosourea-induced rat mammary tumorigenesis. Nutr. Cancer 35, 58-63. https://doi.org/10.1207/S1532791458-63
  11. Conacci-Sorrell, M., Simcha, I., Ben-Yedidia, T., Blechman, J., Savagner, P. and Ben-Ze’ev, A. 2003. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J. Cell Biol. 163, 847-857. https://doi.org/10.1083/jcb.200308162
  12. Dohadwala, M., Wang, G., Heinrich, E., Luo, J., Lau, O., Shih, H., Munaim, Q., Lee, G., Hong, L., Lai, C., Abemayor, E., Fishbein, M. C., Elashoff, D. A., Dubinett, S. M. and St. John, M. A. 2010. The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. Otolaryngol. Head Neck Surg. 142, 753-759. https://doi.org/10.1016/j.otohns.2010.01.034
  13. Fleischauer, A. T. and Arab, L. 2001. Garlic and cancer: a critical review of the epidemiologic literature. J. Nutr. 131, 1032S-1040S.
  14. Fresno Vara, J. A., Casado, E., de, Castro. J., Cejas, P., BeldaIniesta, C. and González-Barón, M. 2004. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30, 193-204. https://doi.org/10.1016/j.ctrv.2003.07.007
  15. Gapter, L. A., Yuin, O. Z. and Ng, K. Y. 2008. S-Allylcysteine reduces breast tumor cell adhesion and invasion. Biochem. Biophys. Res. Commun. 367, 446-451. https://doi.org/10.1016/j.bbrc.2007.12.175
  16. Hanahan, D. and Weinberg, R. A. 2000. The hallmarks of cancer. Cell 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  17. Hatono, S. and Wargovich, M. J. 1997. Role of garlic in disease prevention－preclinical models. Nutraceuticals: Designer Foods III: Garlic, Soy and Licorice. 139-151.
  18. Herman-Antosiewicz, A. and Singh, S. V. 2004. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review. Mutat. Res. 555, 121-131. https://doi.org/10.1016/j.mrfmmm.2004.04.016
  19. Hsing, A. W., Chokkalingam, A. P., Gao, Y. T., Madigan, M. P., Deng, J., Gridley, G. and Fraumeni, J. F. Jr. 2002. Allium vegetables and risk of prostate cancer: a population-based study. J. Natl. Cancer Inst. 94, 1648-1651. https://doi.org/10.1093/jnci/94.21.1648
  20. Iciek, M., Kwiecien, I., Chwatko, G., Sokolowska-Jezewicz, M., Kowalczyk-Pachel, D. and Rokita, H. 2011. The effects of garlic-derived sulfur compounds on cell proliferation, caspase 3 activity, thiol levels and anaerobic sulfur metabolism in human hepatoblastoma HepG2 cells. Cell Biochem. Funct. 30, 198-204.
  21. Jang, T. J., Jeon, K. H. and Jung, K. H. 2009. Cyclooxygenase-2 expression is related to the epithelial-to-mesenchymal transition in human colon cancers. Yonsei Med. J. 50, 818-824. https://doi.org/10.3349/ymj.2009.50.6.818
  22. Jayasurya, R., Francis, G., Kannan, S., Lekshminarayanan, K., Nalinakumari, K. R., Abraham, T., Abraham, E. K. and Nair, M. K. 2004. p53, p16 and cyclin D1: molecular determinants of radiotherapy treatment response in oral carcinoma. Int. J. Cancer 109, 710-716. https://doi.org/10.1002/ijc.20042
  23. Jethwa, P., Naqvi, M., Hardy, R. G., Hotchin, N. A., Roberts, S., Spychal, R. and Tselepis, C. 2008. Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma. World J. Gastroenterol. 14, 1044-1052. https://doi.org/10.3748/wjg.14.1044
  24. Jordà, M., Vinyals, A., Marazuela, A., Cubillo, E., Olmeda, D., Valero, E., Cano, A. and Fabra, A. 2007. Id-1 is induced in MDCK epithelial cells by activated Erk/MAPK pathway in response to expression of the Snail and E47 transcription factors. Exp. Cell Res. 313, 2389-2403. https://doi.org/10.1016/j.yexcr.2007.04.001
  25. Kim, H. H. and Min, G. S. 2015. Inhibitory effects of S-allylcysteine on cell proliferation of human cervical cancer cell line, HeLa. J. Life Sci. 25, 397-405. https://doi.org/10.5352/JLS.2015.25.4.397
  26. Kodera, Y., Suzuki, A., Imada, O., Kasugai, S., Smoke, I., Kanezawa, A., Taru, N., Fujikawa, M., Nagae, S., Masamoto, K., Maeshige, K. and Ono, K. 2002. Physical, chemical, and biological properties of s-allylcysteine, an amino acid derived from garlic. J. Agric. Food Chem. 50, 622-632. https://doi.org/10.1021/jf0106648
  27. Lapenna, S. and Giordano, A. 2009. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 8, 547-566. https://doi.org/10.1038/nrd2907
  28. Lee, B. H. and Lee, S. J. 1999. Preventive effects of a mixed disulphide from dithiocarbamate and N-acetylcysteine on the genotoxicity of N-nitrosodiethylamine. J. Pharm. Pharmacol. 51, 105-109.
  29. Li, Y. J., Wei, Z. M., Meng, Y. X. and Ji, X. R. 2005. Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis. World J. Gastroenterol. 11, 2117-2123. https://doi.org/10.3748/wjg.v11.i14.2117
  30. Liu, Z., Li, M., Chen, K., Yang, J., Chen, R., Wang, T., Liu, J., Yang, W. and Ye, Z. 2012. S-allylcysteine induces cell cycle arrest and apoptosis in androgen-indipendent human prostate cancer cells. Mol. Med. Rep. 5, 439-443.
  31. Llambi, F. and Green, D. R. 2011. Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr. Opin. Genet. Dev. 21, 12-20. https://doi.org/10.1016/j.gde.2010.12.001
  32. Loeppky, R. N. and Li, Y. E. 1991. Nitrosamine activation and detoxication through free radicals and their derived cations. IARC Sci. Publ. 105, 375-382.
  33. Malumbres, M. and Barbacid, M. 2009. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153-166. https://doi.org/10.1038/nrc2602
  34. Martin, K. R. 2006. Targeting apoptosis with dietary bioactive agents. Exp. Biol. Med. (Maywood). 231, 117-129.
  35. McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W., Chang, F., Lehmann, B., Terrian, D. M., Milella, M., Tafuri, A., Stivala, F., Libra, M., Basecke, J., Evangelisti, C., Martelli, A. M. and Franklin, R. A. 2007. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta. 1773, 1263-1284. https://doi.org/10.1016/j.bbamcr.2006.10.001
  36. Moriguchi, T., Matsuura, H., Kodera, Y., Itakura, Y., Katsuki, H., Saito, H. and Nishiyama, N. 1997. Neurotrophic activity of organosulfur compounds having a thioallyl group on cultured rat hippocampal neurons. Neurochem. Res. 22, 1449-1452. https://doi.org/10.1023/A:1021946210399
  37. Na, H. K., Kim, E. H., Choi, M. A., Park, J. M., Kim, D. H. and Surh, Y. J. 2012. Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1. Biochem. Pharmacol. 84, 1241-1250. https://doi.org/10.1016/j.bcp.2012.08.024
  38. Nagae, S., Ushijima, M., Hatono, S., Imai, J., Kasugai, S., Matsuura, H., Itakura, Y. and Higashi, Y. 1994. Pharmacokinetics of the garlic compound S-allylcysteine. Planta. Med. 60, 214-217. https://doi.org/10.1055/s-2006-959461
  39. Neal, C. L., Mckeithen, D. and Odero-Marah, V. A. 2011. Snail negatively regulates cell adhesion to extracellular matrix and integrin expression via the MAPK pathway in prostate cancer cells. Cell Adh. Migr. 5, 249-257. https://doi.org/10.4161/cam.5.3.15618
  40. Ng, K. T., Guo, D. Y., Cheng, Q., Geng, W., Ling, C. C., Li, C. X., Liu, X. B., Ma, Y. Y., Lo, C. M., Poon, R. T., Fan, S. T and Man, K. 2012. A garlic derivative, S-allylcysteine (SAC), suppresses proliferation and metastasis of hepatocellular carcinoma. PLoS One 7, e31655. https://doi.org/10.1371/journal.pone.0031655
  41. Nicholson, K. M. and Anderson, N. G. 2002. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14, 381-395. https://doi.org/10.1016/S0898-6568(01)00271-6
  42. Noori, S. and Hassan, Z. M. 2012. Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis. Free Radic. Biol. Med. 52, 1987-1999. https://doi.org/10.1016/j.freeradbiomed.2012.01.026
  43. Oberley, L. W. and Buettner, G. R. 1979. Role of superoxide dismutase in cancer: a review. Cancer Res. 39, 1141-1149.
  44. Oyama, T., Kanai, Y., Ochiai, A., Akimoto, S., Oda, T., Yanagihara, K., Nagafuchi, A., Tsukita, S., Shibamoto, S., Ito, F. and Takeichi, M., Matsuda, H. and Hirohashi, S. 1994. A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines. Cancer Res. 54, 6282-6287.
  45. Pagliei, B., Aquilano, K., Baldelli, S. and Ciriolo, M. R. 2013. Garlic-derived diallyl disulfide modulates peroxisome proliferator activated receptor gamma co-activator 1 alpha in neuroblastoma cells. Biochem. Pharmacol. 85, 335-344. https://doi.org/10.1016/j.bcp.2012.11.007
  46. Pai, M. H., Kuo, Y. H., Chiang, E. P. and Tang, F. Y. 2012. S-Allylcysteine inhibits tumour progression and the epithelial-mesenchymal transition in a mouse xenograft model of oral cancer. Br. J. Nutr. 108, 28-38. https://doi.org/10.1017/S0007114511005307
  47. Philchenkov, A. 2004. Caspases: potential targets for regulating cell death. J. Cell. Mol. Med. 8, 432-444. https://doi.org/10.1111/j.1582-4934.2004.tb00468.x
  48. Powolny, A. A. and Singh, S. V. 2008. Multitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds. Cancer Lett. 269, 305-314. https://doi.org/10.1016/j.canlet.2008.05.027
  49. Reed, J. C. 2006. Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 13, 1378-1386. https://doi.org/10.1038/sj.cdd.4401975
  50. Sartor, M., Steingrimsdottir, H., Elamin, F., Gäken, J., Warnakulasuriya, S., Partridge, M., Thakker, N., Johnson, N. W. and Tavassoli, M. 1999. Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines. Br. J. Cancer 80, 79-86. https://doi.org/10.1038/sj.bjc.6690505
  51. Sundaresan, S. and Subramanian, P. 2008. Prevention of N-nitrosodiethylamine-induced hepatocarcinogenesis by S-allylcysteine. Mol. Cell Biochem. 310, 209-214. https://doi.org/10.1007/s11010-007-9682-4
  52. Takayama, T., Shiozaki, H., Shibamoto, S., Oka, H., Kimura, Y., Tamura, S., Inoue, M., Monden, T., Ito, F. and Monden, M. 1996. Beta-catenin expression in human cancers. Am. J. Pathol. 148, 39-46.
  53. Tanaka, S., Haruma, K., Yoshihara, M., Kajiyama, G., Kira, K., Amagase, H. and Chayama, K. 2006. Aged garlic extract has potential suppressive effect on colorectal adenomas in humans. J. Nutr. 136, 821S-826S.
  54. Tang, F. Y., Chiang, E. P. and Pai, M. H. 2010. Consumption of S-allylcysteine inhibits the growth of human non-smallcell lung carcinoma in a mouse xenograft model. J. Agric. Food Chem. 58, 11156-11164. https://doi.org/10.1021/jf102539k
  55. Tang, F. Y., Chiang, E. P., Chung, J. G., Lee, H. Z. and Hsu, C. Y. 2009. S-allylcysteine modulates the expression of E-cadherin and inhibits the malignant progression of human oral cancer. J. Nutr. Biochem. 20, 1013-1020. https://doi.org/10.1016/j.jnutbio.2008.09.007
  56. Taylor, R. C., Cullen, S. P. and Martin, S. J. 2008. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9, 231-241. https://doi.org/10.1038/nrm2312
  57. Thomas, G. J. and Speight, P. M. 2001. Cell adhesion molecules and oral cancer. Crit. Rev. Oral Biol. Med. 12, 479-498. https://doi.org/10.1177/10454411010120060301
  58. Thomson, M. and Ali, M. 2003. Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent. Curr. Cancer Drug Targets 3, 67-81. https://doi.org/10.2174/1568009033333736
  59. Todd, R., Hinds, P. W., Munger, K., Rustgi, A. K., Opitz, O. G., Suliman, Y. and Wong, D. T. 2002. Cell cycle dysregulation in oral cancer. Crit. Rev. Oral Biol. Med. 13, 51-61. https://doi.org/10.1177/154411130201300106
  60. Van Aken, E., De Wever, O., Correia da Rocha, A. S. and Mareel, M. 2001. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch. 439, 725-751. https://doi.org/10.1007/s004280100516
  61. Velmurugan, B., Mani, A. and Nagini, S. 2005. Combination of S-allylcysteine and lycopene induces apoptosis by modulating Bcl-2, Bax, Bim and caspases during experimental gastric carcinogenesis. Eur. J. Cancer Prev. 14, 387-393. https://doi.org/10.1097/00008469-200508000-00012
  62. Vivanco, I. and Sawyers, C. L. 2002. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501. https://doi.org/10.1038/nrc839
  63. Welch, C., Wuarin, L. and Sidell, N. 1992. Antiproliferative effect of the garlic compound S-allyl cysteine on human neuroblastoma cells in vitro. Cancer Lett. 63, 211-219. https://doi.org/10.1016/0304-3835(92)90263-U
  64. Xu, Y. S., Feng, J. G., Zhang, D., Luo, M., Su, D. and Lin, N. M. 2014. S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro. Acta. Pharmacol. Sin. 35, 267-274. https://doi.org/10.1038/aps.2013.176
  65. Zhou, Y., Zhuang, W., Hu, W., Liu, G. J., Wu, T. X. and Wu, X. T. 2011. Consumption of large amounts of Allium vegetables reduces risk for gastric cancer in a meta-analysis. Gastroenterology 141, 80-89. https://doi.org/10.1053/j.gastro.2011.03.057