Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti-apoptotic proteins Corrigendum in /10.3892/or.2023.8646 Retraction in /10.3892/or.2024.8728

Račkauskas,Rokas; Zhou,Dachen; Ūselis,Simonas; Strupas,Kęstutis; Herr,Ingrid; Schemmer,Peter

doi:10.3892/or.2017.5622

Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti-apoptotic proteins Corrigendum in /10.3892/or.2023.8646

Retraction in: /10.3892/or.2024.8728

Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti-apoptotic proteins

Corrigendum in: /10.3892/or.2023.8646 Retraction in /10.3892/or.2024.8728

Authors:
- Rokas Račkauskas
- Dachen Zhou
- Simonas Ūselis
- Kęstutis Strupas
- Ingrid Herr
- Peter Schemmer
View Affiliations

Affiliations: Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, D-69120 Heidelberg, Germany, Centre of Abdominal Surgery, Vilnius University, L-08661 Vilnius, Lithuania
Published online on: May 3, 2017 https://doi.org/10.3892/or.2017.5622
Pages: 3660-3666

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

Cholangiocarcinoma (CCC) is an aggressive malignancy with poor therapeutic options and pronounced chemotherapy resistance. The bioactive broccoli substance, sulforaphane (SFN), is a promising new therapeutic option since it has been found to induce therapeutic effects in both experimental and epidemiological studies in various tumor entities. Thus, the present study was designed to assess the effect of SFN on cisplatin sensitivity in CCC. Human HuCCT-1 and TFK-1 cells, representing intrahepatic and extrahepatic CCC, respectively, were treated with cisplatin and SFN. Viability, the platinated DNA content, and apoptosis were assessed using both MTT assay and flow cytometry, while western blotting was used to analyze the expression of proteins involved in apoptosis and DNA damage. Whereas cisplatin was largely ineffective, SFN only therapy significantly decreased the viability of both CCC cell lines. The combination of SFN with cisplatin increased cisplatin cytotoxicity, which was particularly pronounced relatively early at 36 h after treatment. Apoptosis, which was reflected by the cleavage of caspase-3 and PARP, was significantly enhanced. Notably, only cisplatin was found to induce the expression of proteins involved in the DNA damage response; however, the presence of SFN appeared to enable otherwise cisplatin-resistant cells to undergo apoptosis. Due to the fact that SFN did not enhance the DNA platination levels upon cisplatin treatment, SFN may have exerted its activity via the inhibition of the anti-apoptotic proteins Bcl-2 and XIAP, as we observed. Data presented in the present study clearly demonstrated that SFN significantly decreased the drug resistance to cisplatin in human CCC. This highlights dietary co-treatment as a viable new treatment option for CCC.

View Figures

View References

1	Macias RI: Cholangiocarcinoma: Biology, clinical management, and pharmacological perspectives. ISRN Hepatol. 2014:8280742014. View Article : Google Scholar : PubMed/NCBI
2	Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ and Cameron JL: Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 224:463–475. 1996. View Article : Google Scholar : PubMed/NCBI
3	Vogel A, Wege H, Caca K, Nashan B and Neumann U: The diagnosis and treatment of cholangiocarcinoma. Dtsch Arztebl Int. 111:748–754. 2014.PubMed/NCBI
4	DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ and Schulick RD: Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution. Ann Surg. 245:755–762. 2007. View Article : Google Scholar : PubMed/NCBI
5	Eckel F and Schmid RM: Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br J Cancer. 96:896–902. 2007. View Article : Google Scholar : PubMed/NCBI
6	Shi Y, Hu Y, Hu X, Li X, Lin L and Han X: Cisplatin combined with irinotecan or etoposide for untreated extensive-stage small cell lung cancer: A multicenter randomized controlled clinical trial. Thorac Cancer. 6:785–791. 2015. View Article : Google Scholar : PubMed/NCBI
7	Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, et al: Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 71:117–122. 1988.PubMed/NCBI
8	O'Kane GM, Cadoo KA, Walsh EM, Emerson R, Dervan P, O'Keane C, Hurson B, O'Toole G, Dudeney S, Kavanagh E, et al: Perioperative chemotherapy in the treatment of osteosarcoma: A 26-year single institution review. Clin Sarcoma Res. 5:172015. View Article : Google Scholar : PubMed/NCBI
9	Stein A, Arnold D, Bridgewater J, Goldstein D, Jensen LH, Klümpen HJ, Lohse AW, Nashan B, Primrose J, Schrum S, et al: Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 15:5642015. View Article : Google Scholar : PubMed/NCBI
10	Wang D and Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 4:307–320. 2005. View Article : Google Scholar : PubMed/NCBI
11	Siddik ZH: Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene. 22:7265–7279. 2003. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Talalay P, Cho CG and Posner GH: A major inducer of anticarcinogenic protective enzymes from broccoli: Isolation and elucidation of structure. Proc Natl Acad Sci USA. 89:pp. 2399–2403. 1992; View Article : Google Scholar : PubMed/NCBI
13	Fahey JW, Zalcmann AT and Talalay P: The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry. 56:5–51. 2001. View Article : Google Scholar : PubMed/NCBI
14	Juge N, Mithen RF and Traka M: Molecular basis for chemoprevention by sulforaphane: A comprehensive review. Cell Mol Life Sci. 64:1105–1127. 2007. View Article : Google Scholar : PubMed/NCBI
15	Jin CY, Moon DO, Lee JD, Heo MS, Choi YH, Lee CM, Park YM and Kim GY: Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells. Carcinogenesis. 28:1058–1066. 2007. View Article : Google Scholar : PubMed/NCBI
16	Hunakova L, Gronesova P, Horvathova E, Chalupa I, Cholujova D, Duraj J and Sedlak J: Modulation of cisplatin sensitivity in human ovarian carcinoma A2780 and SKOV3 cell lines by sulforaphane. Toxicol Lett. 230:479–486. 2014. View Article : Google Scholar : PubMed/NCBI
17	Rausch V, Liu L, Kallifatidis G, Baumann B, Mattern J, Gladkich J, Wirth T, Schemmer P, Büchler MW, Zöller M, et al: Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics. Cancer Res. 70:5004–5013. 2010. View Article : Google Scholar : PubMed/NCBI
18	Chen H, Landen CN, Li Y, Alvarez RD and Tollefsbol TO: Enhancement of cisplatin-mediated apoptosis in ovarian cancer cells through potentiating G2/M arrest and p21 upregulation by combinatorial epigallocatechin gallate and sulforaphane. J Oncol. 2013:8729572013. View Article : Google Scholar : PubMed/NCBI
19	Miyagiwa M, Ichida T, Tokiwa T, Sato J and Sasaki H: A new human cholangiocellular carcinoma cell line (HuCC-T1) producing carbohydrate antigen 19/9 in serum-free medium. In Vitro Cell Dev Biol. 25:503–510. 1989. View Article : Google Scholar : PubMed/NCBI
20	Saijyo S, Kudo T, Suzuki M, Katayose Y, Shinoda M, Muto T, Fukuhara K, Suzuki T and Matsuno S: Establishment of a new extrahepatic bile duct carcinoma cell line, TFK-1. Tohoku J Exp Med. 177:61–71. 1995. View Article : Google Scholar : PubMed/NCBI
21	Hong ZF, Zhao WX, Yin ZY, Xie CR, Xu YP, Chi XQ, Zhang S and Wang XM: Capsaicin enhances the drug sensitivity of cholangiocarcinoma through the inhibition of chemotherapeutic-induced autophagy. PLoS One. 10:e01215382015. View Article : Google Scholar : PubMed/NCBI
22	Mah LJ, El-Osta A and Karagiannis TC: gammaH2AX: A sensitive molecular marker of DNA damage and repair. Leukemia. 24:679–686. 2010. View Article : Google Scholar : PubMed/NCBI
23	Roberts JJ and Fraval HN: Cisplatin: Current Status and New Developments. Prestayko AW, Crooke ST and Carter SK: Academic Press; Orlando: pp. 57–77. 1980, View Article : Google Scholar
24	Kallifatidis G, Labsch S, Rausch V, Mattern J, Gladkich J, Moldenhauer G, Büchler MW, Salnikov AV and Herr I: Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate. Mol Ther. 19:188–195. 2011. View Article : Google Scholar : PubMed/NCBI
25	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 : PubMed/NCBI
26	Fimognari C, Lenzi M, Sciuscio D, Cantelli-Forti G and Hrelia P: Combination of doxorubicin and sulforaphane for reversing doxorubicin-resistant phenotype in mouse fibroblasts with p53^Ser220 mutation. Ann NY Acad Sci. 1095:62–69. 2007. View Article : Google Scholar : PubMed/NCBI
27	Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 273:5858–5868. 1998. View Article : Google Scholar : PubMed/NCBI
28	Helt CE, Cliby WA, Keng PC, Bambara RA and O'Reilly MA: Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. J Biol Chem. 280:1186–1192. 2005. View Article : Google Scholar : PubMed/NCBI
29	Podhorecka M, Skladanowski A and Bozko P: H2AX phosphorylation: Its role in DNA damage response and cancer therapy. J Nucleic Acids. 2010:9201612010. View Article : Google Scholar : PubMed/NCBI
30	Doerks T, Copley RR, Schultz J, Ponting CP and Bork P: Systematic identification of novel protein domain families associated with nuclear functions. Genome Res. 12:47–56. 2002. View Article : Google Scholar : PubMed/NCBI
31	Khalil HS, Tummala H and Zhelev N: ATM in focus: A damage sensor and cancer target. Biodiscovery. 5(1)2012.doi: 10.7750/BioDiscovery.2012.5.1.
32	Liu X, He Y, Li F, Huang Q, Kato TA, Hall RP and Li CY: Caspase-3 promotes genetic instability and carcinogenesis. Mol Cell. 58:284–296. 2015. View Article : Google Scholar : PubMed/NCBI
33	Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 63:12–31. 2007. View Article : Google Scholar : PubMed/NCBI