Sulforaphane regulates apoptosis- and proliferation‑related signaling pathways and synergizes with cisplatin to suppress human ovarian cancer Retraction in /10.3892/ijmm.2024.5367

Kan,Shi‑Feng; Wang,Jian; Sun,Guan‑Xing

doi:10.3892/ijmm.2018.3860

Sulforaphane regulates apoptosis- and proliferation‑related signaling pathways and synergizes with cisplatin to suppress human ovarian cancer

Retraction in: /10.3892/ijmm.2024.5367

Authors:
- Shi‑Feng Kan
- Jian Wang
- Guan‑Xing Sun
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Affiliations: Department of Oncology, Zaozhuang City Hospital, Zaozhuang, Shandong 277102, P.R. China, Department of Gynecology, Zaozhuang City Hospital, Zaozhuang, Shandong 277102, P.R. China, Department of Oncology, Zaozhuang City Hospital, Zaozhuang, Shandong 277102, P.R. China
Published online on: September 6, 2018 https://doi.org/10.3892/ijmm.2018.3860
Pages: 2447-2458
Copyright: © Kan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ovarian cancer is currently the most life‑threatening type of gynecological malignancy with limited treatment options. Therefore, improved targeted therapies are required to combat ovarian cancer across the world. Sulforaphane is found in raw cruciferous vegetables. The chemotherapeutic and anti‑carcinogenic properties of sulforaphane have been demonstrated, however, the underlying mechanisms remain to be fully elucidated, particularly in ovarian cancer. In the present study, the possibility of repurposing sulforaphane as an anti‑ovarian cancer agent was examined. Cell viability and colony formation assay were used to test the anticancer efficiency of sulforaphane. Then wound healing assay, migration assay, cell cycle and apoptosis assays were used to detect how the drug worked on the cells. The mechanism of sulforaphane was investigated by western blot analysis. It was found that sulforaphane effectively suppressed the progression of human ovarian cancer cell proliferation, migration and cell cycle, and promoted apoptosis. Sulforaphane inhibited multiple cancer‑associated signaling pathways, including B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein, cytochrome c, Caspase‑3, phosphorylated AKT, phosphorylated nuclear factor‑κB, P53, P27, Cyclin‑D1 and cMyc, and reduced the expression levels of human epidermal growth factor receptor 2 in human ovarian cancer cells. Sulforaphane synergized with cisplatin to suppress the cancer cell proliferation and enhance ovarian cancer cell apoptosis. Xenograft experiments in vivo confirmed that sulforaphane effectively suppressed tumor growth by inhibiting ovarian cancer cell proliferation through targeting tumor‑related signals. The results indicated that sulforaphane may be repurposed as an effective anti‑ovarian cancer agent, with further preclinical or clinical investigations required.

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1	Kamieniak MM, Muñoz-Repeto I, Rico D, Osorio A, Urioste M, García-Donas J, Hernando S, Robles-Díaz L and Ramón Y: DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas. Br J Cancer. 108:1732–1742. 2013. View Article : Google Scholar : PubMed/NCBI
2	Pruthi S, Gostout BS and Lindor NM: Identification and management of women with BRCA mutations or hereditary predisposition for breast and ovarian cancer. Mayo Clin Proc. 85:1111–1120. 2010. View Article : Google Scholar : PubMed/NCBI
3	Chester C, Dorigo O, Berek JS and Kohrt H: Immunotherapeutic approaches to ovarian cancer treatment. J Immunother Cancer. 3:72015. View Article : Google Scholar : PubMed/NCBI
4	Gnjatic S, Ritter E, Büchler MW, Giese NA, Brors B, Frei C, Murray A, Halama N, Zörnig I, Chen YT, et al: Seromic profiling of ovarian and pancreatic cancer. Proc Natl Acad Sci USA. 107:5088–5093. 2010. View Article : Google Scholar : PubMed/NCBI
5	Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, et al: Rethinking ovarian cancer: Recommendations for improving outcomes. Nat Rev Cancer. 11:719–725. 2011. View Article : Google Scholar : PubMed/NCBI
6	Frampton JE: Olaparib: A review of its use as maintenance therapy in patients with ovarian cancer. BioDrugs. 29:143–150. 2015. View Article : Google Scholar : PubMed/NCBI
7	Okeke TC, Anyaehie UB and Ezenyeaku CC: Premature menopause. Ann Med Health Sci Res. 3:90–95. 2013. View Article : Google Scholar : PubMed/NCBI
8	Suppipat K, Park CS, Shen Y, Zhu X and Lacorazza HD: Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells. PLoS One. 7:e512512012. View Article : Google Scholar : PubMed/NCBI
9	Clarke JD, Dashwood RH and Ho E: Multi-targeted prevention of cancer by sulforaphane. Cancer Lett. 269:291–304. 2008. View Article : Google Scholar : PubMed/NCBI
10	Myzak MC, Hardin K, Wang R, Dashwood RH and Ho E: Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis. 27:811–819. 2006. View Article : Google Scholar
11	Ho E, Clarke JD and Dashwood RH: Dietary sulforaphane a histone deacetylase inhibitor for cancer prevention. J Nutr. 139:2393–2396. 2009. View Article : Google Scholar : PubMed/NCBI
12	Su ZY, Zhang C, Lee JH, Shu L, Wu TY, Khor TO, Conney AH, Lu YP and Kong AN: Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane. Cancer Prev Res. 7:319–329. 2014. View Article : Google Scholar
13	Atwell LL, Hsu A, Wong CP, Stevens JF, Bella D, Yu TW, Pereira CB, Löhr CV, Christensen JM, Dashwood RH, et al: Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract. Mol Nutr Food Res. 59:424–433. 2015. View Article : Google Scholar :
14	Ho E, Beaver LM, Williams DE and Dashwood RH: Dietary factors and epigenetic regulation for prostate cancer prevention. Adv Nutr. 2:497–510. 2011. View Article : Google Scholar :
15	Hsu A, Wong CP, Yu Z, Williams DE, Dashwood RH and Ho E: Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells. Clin Epigenet. 3:32011. View Article : Google Scholar
16	Li C, Zhou Y, Peng X, Du L, Tian H, Yang G, Niu J and Wu W: Sulforaphane inhibits invasion via activating ERK1/2 signaling in human glioblastoma U87MG and U373MG cells. PLoS One. 9:e905202014. View Article : Google Scholar : PubMed/NCBI
17	Fimognari C, Turrini E, Sestili P, Calcabrini C, Carulli G, Fontanelli G, Rousseau M, Cantelli-Forti G and Hrelia P: Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions. PLoS One. 9:e1019912014. View Article : Google Scholar : PubMed/NCBI
18	Sharma C, Sadrieh L, Priyani A, Ahmed M, Hassan AH and Hussain A: Anti-carcinogenic effects of sulforaphane in association with its apoptosis-inducing and anti-inflammatory properties in human cervical cancer cells. Cancer Epidemiol. 35:272–278. 2011. View Article : Google Scholar
19	Ferreira de Oliveira JM, Remédios C, Oliveira H, Pinto P, Pinho F, Pinho S, Costa M and Santos C: Sulforaphane induces DNA damage and mitotic abnormalities in human osteosarcoma MG-63 cells: Correlation with cell cycle arrest and apoptosis. Nutr Cancer. 66:325–334. 2014. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar
21	Tuefferd M, Couturier J, Penault-Llorca F, Vincent-Salomon A, Broët P, Guastalla JP, Allouache D, Combe M, Weber B, Pujade-Lauraine E, et al: HER2 status in ovarian carcinomas: A multicenter GINECO study of 320 patients. PLoS One. 2:e11382007. View Article : Google Scholar : PubMed/NCBI
22	Kang HS, Huh YM, Kim S and Lee DK: Isolation of RNA aptamers targeting HER2-overexpressing breast cancer cells using cell-SELEX. Bull Korean Chem Soc. 30:1827–1831. 2009. View Article : Google Scholar
23	Chen H, Landen CN, Li Y, Alvarez RD and Tollefsbol TO: Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation. Exp Cell Res. 319:697–706. 2003. View Article : Google Scholar
24	Xu C, Shen G, Chen C, Gélinas C and Kong AN: Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IjBa, IKK pathway in human prostate cancer PC-3 cells. Oncogene. 24:4486–4495. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lee WK and Kim SJ: Sulforaphane regulates differentiation via PI-3K/AKT pathway in human chondrosarcoma cell line, HTB-94 cells. Cancer Prev Res. 18:26–32. 2013.
26	Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B, Cebula-Obrzut B, Smolewski P and Fabianowska-Majewska K: Clofarabine, a novel adenosine analogue, reactivates DNA methylation-silenced tumour suppressor genes and inhibits cell growth in breast cancer cells. Eur J Pharmacol. 723:276–287. 2014. View Article : Google Scholar
27	Suh DH, Lee KH, Kim K, Kang S and Kim JW: Major clinical research advances in gynecologic cancer in 2014. J Gynecol Oncol. 26:156–167. 2015. View Article : Google Scholar : PubMed/NCBI
28	Mahajan N: Fertility preservation in female cancer patients: An overview. J Hum Reprod Sci. 8:3–13. 2015. View Article : Google Scholar : PubMed/NCBI
29	Kamieniak MM, Muñoz-Repeto I, Rico D, Osorio A, Urioste M, García-Donas J, Hernando S, Robles-Díaz L, Ramón Y, Cajal T, Cazorla A, et al: DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas. Br J Cancer. 108:1732–1742. 2013. View Article : Google Scholar : PubMed/NCBI
30	Moyer V; The U.S. Preventive Services Task Force: Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 160:271–281. 2014.
31	Jablonska K, Pula B, Zemla A, Kobierzycki C, Kedzia W, Nowak-Markwitz E, Spaczynski M, Zabel M, Podhorska-Okolow M and Dziegiel P: Expression of the MT1 melatonin receptor in ovarian cancer cells. Int J Mol Sci. 15:23074–23089. 2014. View Article : Google Scholar : PubMed/NCBI
32	Dexheimer TS, Daekyu S and Hurley LH: Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc. 128:5404–5415. 2006. View Article : Google Scholar : PubMed/NCBI
33	Chen T and Wong Y: Selenocystine induces reactive oxygen species-mediated apoptosis in human cancer cells. Biomed Pharmacother. 63:105–113. 2008. View Article : Google Scholar : PubMed/NCBI
34	Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, Mattern J, Li Z, Kolb A, Moldenhauer G, et al: Sulforaphane targets pancreatic tumour-initiating cells by NF-κB-induced antiapoptotic signaling. Gut. 58:949–963. 2009. View Article : Google Scholar
35	Ju W, Wang X, Shi H, Chen W, Belinsky SA and Lin Y: A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor κB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol. 71:1381–1388. 2007. View Article : Google Scholar : PubMed/NCBI
36	Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, Feng B, Brennan C, Weissleder R, Mahmood U, et al: Both p16^Ink4a and the p19^Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA. 103:5947–5952. 2006. View Article : Google Scholar
37	Psyrri A, Bamias A, Yu Z, Weinberger PM, Kassar M, Markakis S, Kowalski D, Efstathiou E, Camp RL, Rimm DL, et al: Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin Cancer Res. 11:8384–8390. 2005. View Article : Google Scholar : PubMed/NCBI
38	Zhou X, Zhang Z, Yang X, Chen W and Zhang P: Inhibition of cyclin D1 expression by cyclin D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin chemosensitivity. Int J Cancer. 124:483–489. 2009. View Article : Google Scholar
39	Biliran H Jr, Wang Y, Banerjee S, Xu H, Heng H, Thakur A, Bollig A, Sarkar FH and Liao JD: Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line. Clin Cancer Res. 11:6075–6086. 2005. View Article : Google Scholar : PubMed/NCBI
40	Luo H, Rankin GO, Juliano N, Jiang BH and Chen YC: Kaempferol inhibits VEGF expression and in vitro angiogenesis through a novel ERK-NFκB-cMyc-p21 pathway. Food Chem. 130:321–328. 2012. View Article : Google Scholar
41	Chen T and Wong YS: Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. J Agric Food Chem. 56:10574–10581. 2008. View Article : Google Scholar : PubMed/NCBI