Saleh A. Almatroodi
Bioactive Compounds of Garlic: Role in The Management of Various Types of Cancer
DOI URL: https://doi.org/10.46424/pharmanest.11.1.2020.1-13
Keywords: Allicin, Diallyl sulfide, Diallyl disulfide, Cancer
Allium Sativum L., well known as garlic, a member of the family Liliaceae, is one of the most commonly used spice and plant-based medicine worldwide. The health promoting effects of allicin, diallyl sulfide, diallyl disulfide and diallyl trisulfide, the principal active component of garlic has been established through its antioxidant potential. Moreover, bioactive compounds of garlic have shown their therapeutic implications in chemically induced carcinogenesis in animal models through suppression or inhibition of promotion and progression of carcinogenesis. Moreover, bioactive compound has revealed chemopreventive effect on various types of tumour including breast, liver, skin, pancreas, oral and prostate through inhibiting the cell proliferation. This review summarizes the mechanism of action and anti-cancerous effects of allicin, ajoene, diallyl sulfide, diallyl disulfide and diallyl trisulfide on different types of cancer. Further studies based on animal model are warranted to evaluate the efficacy, safety and mechanism of action of bioactive compound in tumour management.
1. Vissink, A., et al., Oral Sequelae of Head and Neck Radiotherapy. Critical Reviews in Oral Biology & Medicine, 2003. 14(3): p. 199-212.
2. Hong, Y.-S., et al., Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. Experimental & Molecular Medicine, 2000. 32(3): p. 127-134.
3. Farhadi, F., et al., Garlic ((Allium sativum)) Fresh Juice Induces Apoptosis in Human Oral Squamous Cell Carcinoma: The Involvement of Caspase-3, Bax and Bcl-2. J Dent Res Dent Clin Dent Prospects, 2015. 9(4): p. 267-73.
4. Dong, M., et al., Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomed Rep, 2014. 2(2): p. 250-254.
5. Jikihara, H., et al., Aged garlic extract inhibits 1,2-dimethylhydrazine-induced colon tumor development by suppressing cell proliferation. Oncol Rep, 2015. 33(3): p. 1131-40.
6. Mousa, A.S. and S.A. Mousa, Anti-angiogenesis efficacy of the garlic ingredient alliin and antioxidants: role of nitric oxide and p53. Nutr Cancer, 2005. 53(1): p. 104-10.
7. Liao, Q.-J., et al., Effect of diallyl disulfide on cell cycle arrest of human colon cancer SW480 cells. Ai Zheng, 2009. 28(2): p. 138-141.
8. Stiles, B., et al., PTENless means more. Developmental biology, 2004. 273(2): p. 175-184.
9. Downes, C.P., et al., Stimulation of PI 3-kinase signaling via inhibition of the tumor suppressor phosphatase, PTEN. Advances in enzyme regulation, 2007. 1(47): p. 184-194.
10. Zhang, Y., et al., Garlic‑derived compound S‑allylmercaptocysteine inhibits cell growth and induces apoptosis via the JNK and p38 pathways in human colorectal carcinoma cells. Oncology letters, 2014. 8(6): p. 2591-2596.
11. Lee, C.G., et al., Allicin inhibits invasion and migration of breast cancer cells through the suppression of VCAM-1: Regulation of association between p65 and ER-α. Journal of functional foods, 2015. 15: p. 172-185.
12. Tsubura, A., et al., Anticancer effects of garlic and garlic-derived compounds for breast cancer control. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 2011. 11(3): p. 249-253.
13. LEI, X.y., et al., Apoptosis induced by diallyl disulfide in human breast cancer cell line MCF‐7 1. Acta pharmacologica Sinica, 2008. 29(10): p. 1233-1239.
14. Nakagawa, H., et al., Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines. Carcinogenesis, 2001. 22(6): p. 891-897.
15. Altonsy, M.O., T.N. Habib, and S.C. Andrews, Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone deacetylation. Nutrition and cancer, 2012. 64(8): p. 1251-1260.
16. Na, H.-K., et al., Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1. Biochemical pharmacology, 2012. 84(10): p. 1241-1250.
17. Xiao, X., et al., Diallyl disulfide suppresses SRC/Ras/ERK signaling-mediated proliferation and metastasis in human breast cancer by up-regulating miR-34a. PLoS One, 2014. 9(11): p. e112720.
18. Huang, J., et al., Diallyl disulfide inhibits growth and metastatic potential of human triple‐negative breast cancer cells through inactivation of the β‐catenin signaling pathway. Molecular nutrition & food research, 2015. 59(6): p. 1063-1075.
19. Li, X., et al., Diallyl Trisulfide inhibits breast cancer stem cells via suppression of Wnt/β‐catenin pathway. Journal of cellular biochemistry, 2018. 119(5): p. 4134-4141.
20. Hu, X., et al., Induction of glutathione S‐transferase π as a bioassay for the evaluation of potency of inhibitors of benzo (a) pyrene‐induced cancer in a murine model. International journal of cancer, 1997. 73(6): p. 897-902.
21. Li, C., et al., Allicin induces apoptosis through activation of both intrinsic and extrinsic pathways in glioma cells. Molecular medicine reports, 2018. 17(4): p. 5976-5981.
22. Cha, J.H., et al., Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway. Oncology reports, 2012. 28(1): p. 41-48.
23. Gao, X.-Y., et al., Effect of combined treatment with cyclophosphamidum and allicin on neuroblastoma–bearing mice. Asian Pacific journal of tropical medicine, 2015. 8(2): p. 137-141.
24. Welch, C., L. Wuarin, and N. Sidell, Antiproliferative effect of the garlic compound S-allyl cysteine on human neuroblastoma cells in vitro. Cancer letters, 1992. 63(3): p. 211-219.
25. Filomeni, G., et al., Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer research, 2003. 63(18): p. 5940-5949.
26. Tao, Q., et al., Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of glioma cells by inactivating Wnt/β-catenin signaling. Cell and tissue research, 2017. 370(3): p. 379-390.
27. Li, Y., et al., Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of osteosarcoma cells by switching on suppressor microRNAs and inactivating of Notch-1 signaling. Carcinogenesis, 2013. 34(7): p. 1601-10.
28. Li, Y., et al., Diallyl disulfide suppresses FOXM1-mediated proliferation and invasion in osteosarcoma by upregulating miR-134. J Cell Biochem, 2018.
29. Xie, W.P., et al., Treatment of Saos-2 osteosarcoma cells with diallyl trisulfide is associated with an increase in calreticulin expression. Exp Ther Med, 2018. 15(6): p. 4737-4742.
30. Wang, H., et al., Diallyl trisulfide induces osteosarcoma cell apoptosis through reactive oxygen species-mediated downregulation of the PI3K/Akt pathway. Oncol Rep, 2016. 35(6): p. 3648-58.
31. Jiang, W., et al., The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Asian Pac J Cancer Prev, 2013. 14(8): p. 4615-9.
32. Wu, P.-P., et al., Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase-and mitochondria-dependent pathways. International Journal of Oncology, 2011. 38(6): p. 1605-1613.
33. Lin, Y.-T., et al., Diallyl disulfide (DADS) induces apoptosis in human cervical cancer Ca Ski cells via reactive oxygen species and Ca2+-dependent mitochondria-dependent pathway. Anticancer research, 2008. 28(5A): p. 2791-2799.
34. Di, C., et al., Diallyl disulfide enhances carbon ion beams-induced apoptotic cell death in cervical cancer cells through regulating Tap73 /DeltaNp73. Cell Cycle, 2015. 14(23): p. 3725-33.
35. Zhang, Q. and D. Yang, Allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2. Exp Ther Med, 2019. 17(3): p. 1523-1528.
36. Shirin, H., et al., Antiproliferative effects of S-allylmercaptocysteine on colon cancer cells when tested alone or in combination with sulindac sulfide. Cancer research, 2001. 61(2): p. 725-731.
37. Yang, J.-S., et al., Diallyl disulfide induces apoptosis in human colon cancer cell line (COLO 205) through the induction of reactive oxygen species, endoplasmic reticulum stress, caspases casade and mitochondrial-dependent pathways. Food and Chemical Toxicology, 2009. 47(1): p. 171-179.
38. Hosono, T., et al., Diallyl trisulfide suppresses the proliferation and induces apoptosis of human colon cancer cells through oxidative modification of β-tubulin. Journal of Biological Chemistry, 2005. 280(50): p. 41487-41493.
39. Huang, Y.-S., et al., Diallyl disulfide inhibits the proliferation of HT-29 human colon cancer cells by inducing differentially expressed genes. Molecular medicine reports, 2011. 4(3): p. 553-559.
40. Yu, C.-S., et al., Diallyl trisulfide induces apoptosis in human primary colorectal cancer cells. Oncology reports, 2012. 28(3): p. 949-954.
41. Zhang, Q., et al., Wnt/β-catenin signaling mediates the suppressive effects of diallyl trisulfide on colorectal cancer stem cells. Cancer chemotherapy and pharmacology, 2018. 81(6): p. 969-977.
42. Wargovich, M.J., Diallyl sulfide, a flavor component of garlic (Allium sativum), inhibits dimethyihydrazine-induced colon cancer. Carcinogenesis, 1987. 8(3): p. 487-489.
43. Li, N., et al., A proteomic investigation into a human gastric cancer cell line BGC823 treated with diallyl trisulfide. Carcinogenesis, 2006. 27(6): p. 1222-1231.
44. Su, B., et al., Identification of potential targets for diallyl disulfide in human gastric cancer MGC-803 cells using proteomics approaches. Oncology reports, 2015. 33(5): p. 2484-2494.
45. Pan, Y., et al., Epigenetic upregulation of metallothionein 2A by diallyl trisulfide enhances chemosensitivity of human gastric cancer cells to docetaxel through attenuating NF-κB activation. Antioxidants & redox signaling, 2016. 24(15): p. 839-854.
46. Jiang, X.-y., et al., Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment. Acta Pharmacologica Sinica, 2017. 38(7): p. 1048.
47. Jiang, X., et al., Diallyl trisulfide inhibits growth of NCI-H460 in vitro and in vivo, and ameliorates cisplatin-induced oxidative injury in the treatment of lung carcinoma in xenograft mice. International journal of biological sciences, 2017. 13(2): p. 167.
48. Ling, H., et al., Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803. Cellular & molecular biology letters, 2006. 11(3): p. 408.
49. Sun, L. and X. Wang, Effects of allicin on both telomerase activity and apoptosis in gastric cancer SGC-7901 cells. World journal of gastroenterology, 2003. 9(9): p. 1930.
50. Zhang, X., et al., Allicin induces apoptosis of the MGC-803 human gastric carcinoma cell line through the p38 mitogen-activated protein kinase/caspase-3 signaling pathway. Molecular medicine reports, 2015. 11(4): p. 2755-2760.
51. Song, B., et al., Allicin inhibits human renal clear cell carcinoma progression via suppressing HIF pathway. International journal of clinical and experimental medicine, 2015. 8(11): p. 20573.
52. Chu, Y.-L., et al., Allicin induces anti-human liver cancer cells through the p53 gene modulating apoptosis and autophagy. Journal of agricultural and food chemistry, 2013. 61(41): p. 9839-9848.
53. Zou, X., et al., Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway. Journal of Pharmacological Sciences, 2016. 131(4): p. 233-240.
54. Wu, C.-C., et al., Differential effects of allyl sulfides from garlic essential oil on cell cycle regulation in human liver tumor cells. Food and Chemical Toxicology, 2004. 42(12): p. 1937-1947.
55. Yu, F.-S., et al., Diallyl sulfide inhibits murine WEHI-3 leukemia cells in BALB/c mice in vitro and in vivo. Human & experimental toxicology, 2009. 28(12): p. 785-790.
56. Hung, F.M., et al., Effects of diallyl trisulfide on induction of apoptotic death in murine leukemia WEHI‐3 cells in vitro and alterations of the immune responses in normal and leukemic mice in vivo. Environmental toxicology, 2015. 30(11): p. 1343-1353.
57. Tan, H., et al., Inhibition of ERK and activation of p38 are involved in diallyl disulfide induced apoptosis of leukemia HL-60 cells. Archives of pharmacal research, 2008. 31(6): p. 786.
58. Suda, S., et al., Identification of molecular target of diallyl trisulfide in leukemic cells. Bioscience, biotechnology, and biochemistry, 2014. 78(8): p. 1415-1417.
59. Choi, Y.H. and H.S. Park, Apoptosis induction of U937 human leukemia cells by diallyl trisulfide induces through generation of reactive oxygen species. Journal of biomedical science, 2012. 19(1): p. 50.
60. Dirsch, V., et al., Ajoene, an experimental anti-leukemic drug: mechanism of cell death. Leukemia, 2002. 16(1): p. 74.
61. Huang, L., et al., Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling. Oncology letters, 2017. 14(1): p. 468-474.
62. Xiao, D., et al., Diallyl trisulfide selectively causes Bax‐and Bak‐mediated apoptosis in human lung cancer cells. Environmental and molecular mutagenesis, 2009. 50(3): p. 201-212.
63. Li, W., et al., Diallyl trisulfide induces apoptosis and inhibits proliferation of A549 cells in vitro and in vivo. Acta Biochim Biophys Sin, 2012. 44(7): p. 577-583.
64. Jin, Z.-Y., et al., Raw garlic consumption as a protective factor for lung cancer, a population-based case–control study in a Chinese population. Cancer prevention research, 2013. 6(7): p. 711-718.
65. Myneni, A.A., et al., Raw garlic consumption and lung cancer in a Chinese population. Cancer Epidemiology and Prevention Biomarkers, 2016. 25(4): p. 624-633.
66. Tang, F.-Y., E.-P. Chiang, and M.-H. Pai, Consumption of S-allylcysteine inhibits the growth of human non-small-cell lung carcinoma in a mouse xenograft model. Journal of agricultural and food chemistry, 2010. 58(20): p. 11156-11164.
67. Dasgupta, P. and S. Sengupta, Role of diallyl disulfide-mediated cleavage of c-Myc and Sp-1 in the regulation of telomerase activity in human lymphoma cell line U937. Nutrition, 2015. 31(7-8): p. 1031-1037.
68. Shigemi, Z., et al., Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma. International journal of oncology, 2016. 48(1): p. 293-304.
69. Rahmani, A.H., et al., Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. BioMed research international, 2014. 2014.
70. Rahmani, A.H., et al., Implications of green tea and its constituents in the prevention of cancer via the modulation of cell signalling pathway. BioMed Research International, 2015. 2015.
71. Rahmani, A.H., et al., Therapeutic effects of date fruits (Phoenix dactylifera) in the prevention of diseases via modulation of anti-inflammatory, anti-oxidant and anti-tumour activity. International journal of clinical and experimental medicine, 2014. 7(3): p. 483.
72. Rahmani, A.H., M.A. Alsahli, and S.A. Almatroodi, Potential antitumor effects of pomegranates and its ingredients. Pharmacognosy reviews, 2017. 11(22): p. 136.
73. Almatroudi, A., et al., Ginger: A Novel Strategy to Battle Cancer through Modulating Cell Signalling Pathways: A Review. Current pharmaceutical biotechnology, 2019. 20(1): p. 5-16.
74. Pai, M.-H., et al., S-Allylcysteine inhibits tumour progression and the epithelial–mesenchymal transition in a mouse xenograft model of oral cancer. British Journal of Nutrition, 2012. 108(1): p. 28-38.
75. Xu, Y.S., et al., S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro. Acta Pharmacol Sin, 2014. 35(2): p. 267-74.
76. Xu, Y., et al., S-allylcysteine suppresses ovarian cancer cell proliferation by DNA methylation through DNMT1. J Ovarian Res, 2018. 11(1): p. 39.
77. Wan, H.F., et al., Effect of diallyl trisulfide on human ovarian cancer SKOV- 3/DDP cell apoptosis. Asian Pac J Cancer Prev, 2013. 14(12): p. 7197-201.
78. Xu, L., et al., Role of JNK activation and mitochondrial Bax translocation in allicin-induced apoptosis in human ovarian cancer SKOV3 cells. Evidence-Based Complementary and Alternative Medicine, 2014. 2014.
79. Wang, C.J., et al., Effect of combined treatment with recombinant interleukin-2 and allicin on pancreatic cancer. Mol Biol Rep, 2013. 40(12): p. 6579-85.
80. Ma, H.-B., et al., Apoptotic pathway induced by diallyl trisulfide in pancreatic cancer cells. World Journal of Gastroenterology: WJG, 2014. 20(1): p. 193.
81. Stan, S., Garlic-derived organosulfur compound diallyl trisulfide induces apoptosis in pancreatic cancer cells. 2013, Federation of American Societies for Experimental Biology.
82. Arunkumar, A., et al., Growth suppressing effect of garlic compound diallyl disulfide on prostate cancer cell line (PC-3) in vitro. Biological and Pharmaceutical Bulletin, 2005. 28(4): p. 740-743.
83. Arunkumar, A., et al., Garlic compound, diallyl disulfide induces cell cycle arrest in prostate cancer cell line PC-3. Molecular and cellular biochemistry, 2006. 288(1-2): p. 107-113.
84. Stan, S.D. and S.V. Singh, Transcriptional repression and inhibition of nuclear translocation of androgen receptor by diallyl trisulfide in human prostate cancer cells. Clinical Cancer Research, 2009. 15(15): p. 4895-4903.
85. Gunadharini DN, A.A., Krishnamoorthy G, Muthuvel R, Vijayababu MR, Kanagaraj P, Srinivasan N, Aruldhas MM, Arunakaran J., Antiproliferative effect of diallyl disulfide (DADS) on prostate cancer cell line LNCaP. Cell Biochem Funct., 2006.
86. Xiao, D., et al., Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Oncogene, 2004. 23(33): p. 5594.
87. Kim, Y.-A., et al., Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak. Molecular cancer therapeutics, 2007. 6(5): p. 1599-1609.
88. Xiao, D. and S. Singh, Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. Carcinogenesis, 2006. 27(3): p. 533.
89. Borkowska, A., N. Knap, and J. Antosiewicz, Diallyl trisulfide is more cytotoxic to prostate cancer cells PC-3 than to noncancerous epithelial cell line PNT1A: a possible role of p66Shc signaling axis. Nutrition and cancer, 2013. 65(5): p. 711-717.
90. Howard, E.W., et al., Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer. Clinical Cancer Research, 2007. 13(6): p. 1847-1856.
91. Wang, H.C., et al., Allyl sulfides inhibit cell growth of skin cancer cells through induction of DNA damage mediated G2/M arrest and apoptosis. Journal of agricultural and food chemistry, 2010. 58(11): p. 7096-7103.
92. Shan, Y., et al., Prophylaxis of diallyl disulfide on skin carcinogenic model via p21-dependent Nrf2 stabilization. Scientific reports, 2016. 6: p. 35676.
93. Shrotriya, S., et al., Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling. Cancer research, 2010. 70(5): p. 1932-1940.
94. Dwivedi, C., et al., Chemoprevention of chemically induced skin tumor development by diallyl sulfide and diallyl disulfide. Pharmaceutical research, 1992. 9(12): p. 1668-1670.
95. Arora, A., I.A. Siddiqui, and Y. Shukla, Modulation of p53 in 7, 12-dimethylbenz [a] anthracene–induced skin tumors by diallyl sulfide in Swiss albino mice. Molecular Cancer Therapeutics, 2004. 3(11): p. 1459-1466.
96. Kalra, N., A. Arora, and Y. Shukla, Involvement of multiple signaling pathways in diallyl sulfide mediated apoptosis in mouse skin tumors. 2006.
97. Hakimzadeh, H., et al., Cytotoxic effect of garlic extract and its fractions on Sk-mel3 melanoma cell line. Immunopharmacology and immunotoxicology, 2010. 32(3): p. 371-375.
98. Xiang, Y., et al., Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer. Experimental and therapeutic medicine, 2018. 15(4): p. 3537-3543.
99. Shin, H.A., et al., Diallyl sulfide induces growth inhibition and apoptosis of anaplastic thyroid cancer cells by mitochondrial signaling pathway. Oral oncology, 2010. 46(4): p. e15-e18.
100. Pan, J., et al., Induction of Apoptosis in Human Papillary-Thyroid-Carcinoma BCPAP Cells by Diallyl Trisulfide through Activation of the MAPK Signaling Pathway. Journal of agricultural and food chemistry, 2018. 66(23): p. 5871-5878.
101. Shin, D.Y., et al., Diallyl trisulfide-induced apoptosis of bladder cancer cells is caspase-dependent and regulated by PI3K/Akt and JNK pathways. Environmental toxicology and pharmacology, 2014. 37(1): p. 74-83.
102. Wang, Y.-B., et al., Diallyl trisulfide induces Bcl-2 and caspase-3-dependent apoptosis via downregulation of Akt phosphorylation in human T24 bladder cancer cells. Phytomedicine, 2010. 17(5): p. 363-368.
103. Jian, W., et al., Effect of Allicin in antagonizing mice’s bladder cancer in vitro and in vivo. Chinese Journal of Integrative Medicine, 2004. 10(3): p. 208-212.