Diallyl disulfide induces G2/M arrest and promotes apoptosis through the p53/p21 and MEK-ERK pathways in human esophageal squamous cell carcinoma

Yin,Xiaoran; Zhang,Rong; Feng,Cheng; Zhang,Jun; Liu,Dong; Xu,Kun; Wang,Xijing; Zhang,Shuqun; Li,Zongfang; Liu,Xinlian; Ma,Hongbing

doi:10.3892/or.2014.3361

Diallyl disulfide induces G2/M arrest and promotes apoptosis through the p53/p21 and MEK-ERK pathways in human esophageal squamous cell carcinoma

Authors:
- Xiaoran Yin
- Rong Zhang
- Cheng Feng
- Jun Zhang
- Dong Liu
- Kun Xu
- Xijing Wang
- Shuqun Zhang
- Zongfang Li
- Xinlian Liu
- Hongbing Ma
View Affiliations

Affiliations: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China, Department of Digestion, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: July 25, 2014 https://doi.org/10.3892/or.2014.3361
Pages: 1748-1756

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with high incidence and mortality worldwide. Diallyl disulfide (DADS) is a natural organosulfur compound, isolated from garlic. In this study, MTT assay showed that DADS significantly reduced cell viability in a dose- and time-dependent manner in ESCC cells, with lower toxicity in normal liver cells. Cell cycle analysis revealed that DADS made G2/M phase arrest. Molecular analysis suggested that this cell cycle arrest was likely made by the decrease of cyclin B1, cdc2, p-cdc2, cdc25c in concomitance with activation of the p53/p21 pathway. Apoptosis was detected by Annexin V/PI staining. The molecule markers showed that DADS induced apoptosis through activating caspases, altering the Bax/Bcl-2 balance and suppressing the MEK-ERK pathway. Our data indicated that DADS has the potential to be an effective and safe anticancer agent for ESCC therapy in the near future.

View Figures

View References

1	Cui X, Zhao Z, Liu D, et al: Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma. J Exp Clin Cancer Res. 33:20–33. 2014. View Article : Google Scholar : PubMed/NCBI
2	Orditura M, Galizia G, Fabozzi A, et al: Preoperative treatment of locally advanced esophageal carcinoma. Int J Oncol. 43:1745–1753. 2013.PubMed/NCBI
3	Matés JM, Segura JA, Alonso FJ and Márquez J: Anticancer antioxidant regulatory functions of phytochemicals. Current Medicinal Chemistry. 18:2315–2338. 2011.PubMed/NCBI
4	Zhou Y, Su J, Shi L, Liao Q and Su Q: DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep. 29:605–612. 2013.PubMed/NCBI
5	Alam M, Zubair S, Farazuddin M, et al: Development, characterization and efficacy of niosomal diallyl disulfide in treatment of disseminated murine candidiasis. Nanomedicine. 9:247–256. 2013. View Article : Google Scholar : PubMed/NCBI
6	Maldonado PD, Chánez-Cárdenas ME and Pedraza-Chaverrí J: Aged garlic extract, garlic powder extract, S-allylcysteine, diallyl sulfide and diallyl disulfide do not interfere with the antibiotic activity of gentamicin. Phytother Res. 19:252–254. 2005. View Article : Google Scholar
7	Lissiman E, Bhasale AL and Cohen M: Garlic for the common cold. Cochrane Database Syst Rev. 3:CD0062062012.
8	Lee IC, Kim SH, Baek HS, et al: The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats. Food Chem Toxicol. 63:174–185. 2014. View Article : Google Scholar
9	Truong D, Hindmarsh W and O’Brien PJ: The molecular mechanisms of diallyl disulfide and diallyl sulfide induced hepatocyte cytotoxicity. Chem Biol Interact. 180:79–88. 2009. View Article : Google Scholar : PubMed/NCBI
10	Arunkumar R, Sharmila G, Elumalai P, et al: Effect of diallyl disulfide on insulin-like growth factor signaling molecules involved in cell survival and proliferation of human prostate cancer cells in vitro and in silico approach through docking analysis. Phytomedicine. 19:912–923. 2012. View Article : Google Scholar
11	Song JD, Lee SK, Kim KM, et al: Molecular mechanism of diallyl disulfide in cell cycle arrest and apoptosis in HCT-116 colon cancer cells. J Biochem Mol Toxicol. 23:71–79. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nkrumah-Elie YM, Reuben JS, Hudson AM, et al: The attenuation of early benzo (a) pyrene-induced carcinogenic insults by diallyl disulfide (DADS) in MCF-10A cells. Nutr Cancer. 64:1112–1121. 2012. View Article : Google Scholar
13	Ling H, Wen L, Ji XX, et al: Growth inhibitory effect and Chk1-dependent signaling involved in G2/M arrest on human gastric cancer cells induced by diallyl disulfide. Braz J Med Biol Res. 43:271–278. 2010. View Article : Google Scholar
14	Jun Z, Suzuki M, Xiao J, Wen J, Talbot SG, Li GC and Xu M: Comparative effects of natural and synthetic diallyl disulfide on apoptosis of human breast-cancer MCF-7 cells. Biotechnol Appl Biochem. 52:113–119. 2009. View Article : Google Scholar : PubMed/NCBI
15	Zhang XH, Zou ZQ, Xu CW, Shen YZ and Li D: Myricetin induces G2/M phase arrest in HepG2 cells by inhibiting the activity of the cyclin B/cdc2 complex. Mol Med Rep. 4:273–277. 2011.PubMed/NCBI
16	Sankari SL, Masthan KM, Babu NA, Bhattacharjee T and Elumalai M: Apoptosis in cancer - an update. Asian Pac J Cancer Prev. 13:4873–4878. 2012. View Article : Google Scholar : PubMed/NCBI
17	Czepukojc B, Baltes AK, Cerella C, et al: Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells. Food Chem Toxicol. 64:249–257. 2014. View Article : Google Scholar
18	Tang H, Kong Y, Guo J, et al: Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by upregulation of miR-200b and miR-22. Cancer Lett. 340:72–81. 2013. View Article : Google Scholar
19	Haneji T, Hirashima K, Teramachi J and Morimoto H: Okadaic acid activates the PKR pathway and induces apoptosis through PKR stimulation in MG63 osteoblast-like cells. Int J Oncol. 42:1904–1910. 2013.PubMed/NCBI
20	Hui C, Jun W, Ya LN and Ming X: Effect of Allium sativum (garlic) diallyl disulfide (DADS) on human non-small cell lung carcinoma H1299 cells. Trop Biomed. 25:37–45. 2008.
21	Tan H, Ling H, He J, Yi L, Zhou J, Lin M and Su Q: Inhibition of ERK and activation of p38 are involved in diallyl disulfide induced apoptosis of leukemia HL-60 cells. Arch Pharm Res. 31:786–793. 2008. View Article : Google Scholar : PubMed/NCBI
22	Altonsy MO, Habib TN and Andrews SC: Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone deacetylation. Nutr Cancer. 64:1251–1260. 2012. View Article : Google Scholar
23	Duong HQ, Hwang JS, Kim HJ, Seong YS and Bae I: BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells. Int J Oncol. 41:2227–2236. 2012.PubMed/NCBI
24	Paul P, Rajendran SK, Peuhu E, Alshatwi AA, Akbarsha MA, Hietanen S and Eriksson JE: Novel action modality of the diterpenoid anisomelic acid causes depletion of E6 and E7 viral oncoproteins in HPV-transformed cervical carcinoma cells. Biochem Pharmacol. 89:171–184. 2014. View Article : Google Scholar
25	Zhang Z, Wang CZ, Du GJ, et al: Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol. 43:289–296. 2013.PubMed/NCBI
26	Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS and Du W: Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett. 301:185–192. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ding L, Huang Y, Du Q, et al: TGEV nucleocapsid protein induces cell cycle arrest and apoptosis through activation of p53 signaling. Biochem Biophys Res Commun. 445:497–503. 2014. View Article : Google Scholar : PubMed/NCBI
28	Takahashi H, Chen MC, Pham H, et al: Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 downregulation in human pancreatic cancer cells. Biochim Biophys Acta. 1813:1465–1474. 2011.
29	Lv C, Sun W, Sun H, Wei S, Chen R, Wang B and Huang C: Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway. Mar Drugs. 11:316–331. 2013. View Article : Google Scholar