Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor‑κB pathway in SKOV3PT platinum‑resistant human ovarian cancer cells

Zhong,Yan‑Ying; Chen,He‑Ping; Tan,Bu‑Zhen; Yu,Hai‑Hong; Huang,Xiao‑Shan

doi:10.3892/ol.2013.1524

Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor‑κB pathway in SKOV3PT platinum‑resistant human ovarian cancer cells

Authors:
- Yan‑Ying Zhong
- He‑Ping Chen
- Bu‑Zhen Tan
- Hai‑Hong Yu
- Xiao‑Shan Huang
View Affiliations

Affiliations: The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 12, 2013 https://doi.org/10.3892/ol.2013.1524
Pages: 1084-1092

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

An acquired resistance to platinum‑based drugs has emerged as a significant impediment to effective ovarian cancer therapy. The present study explored the anticancer mechanisms of triptolide (TPL) in SKOV3PT platinum‑resistant human ovarian cancer cells and observed that TPL activated caspase 3 and induced the dose‑dependent apoptosis of the SKOV3PT cells. Furthermore, TPL inhibited complex I of the mitochondrial respiratory chain (MRC) followed by an increase of reactive oxygen species (ROS), which further inhibited nuclear factor (NF)‑κB activation and resulted in the downregulation of anti‑apoptotic proteins, Bcl‑2 and X‑linked inhibitor of apoptosis protein (XIAP). Notably, the pre‑treatment with N‑acetyl‑L‑cysteine (NAC) abolished the TPL‑induced ROS generation, NF‑κB inhibition and cell apoptosis, but did not affect the inhibitory effect of TPL on complex I activity. These results suggested that TPL negatively regulated the NF‑κB pathway through mitochondria‑derived ROS accumulation, promoting the apoptosis of the SKOV3PT cells. Furthermore, TPL synergistically enhanced the cytotoxicity of cisplatin against platinum‑resistant ovarian cancer cells. Collectively, these findings suggest that TPL is able to overcome chemoresistance and that it may be an effective treatment for platinum‑resistant ovarian cancer, either alone or as an adjuvant therapy.

View Figures

View References

1	Cannistra SA: Cancer of the ovary. N Engl J Med. 351:2519–2529. 2004. View Article : Google Scholar : PubMed/NCBI
2	Shepherd JE: Current strategies for prevention, detection, and treatment of ovarian cancer. J Am Pharm Assoc (Wash). 40:392–401. 2000.PubMed/NCBI
3	Agarwal R and Kaye SB: Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 3:502–516. 2003. View Article : Google Scholar : PubMed/NCBI
4	Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 22:7265–7279. 2003. View Article : Google Scholar : PubMed/NCBI
5	Brabec V and Kasparkova J: Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist Updat. 8:131–146. 2005. View Article : Google Scholar : PubMed/NCBI
6	White KL, Rider DN, Kalli KR, Knutson KL, Jarvik GP and Goode EL: Genomics of the NF-κB signaling pathway: hypothesized role in ovarian cancer. Cancer Causes Control. 22:785–801. 2011.
7	Nakanishi C and Toi M: Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer. 5:297–309. 2005. View Article : Google Scholar : PubMed/NCBI
8	Li F and Sethi G: Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta. 1805:167–180. 2010.PubMed/NCBI
9	Baud V and Karin M: Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 8:33–40. 2009. View Article : Google Scholar : PubMed/NCBI
10	Yeh PY, Chuang SE, Yeh KH, Song YC, Ea CK and Cheng AL: Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation. Biochem Pharmacol. 63:1423–1430. 2002. View Article : Google Scholar : PubMed/NCBI
11	Chen BJ: Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma. 42:253–265. 2001. View Article : Google Scholar : PubMed/NCBI
12	Chen YW, Lin GJ, Chia WT, Lin CK, Chuang YP and Sytwu HK: Triptolide exerts anti-tumor effect on oral cancer and KB cells in vitro and in vivo. Oral Oncol. 45:562–568. 2009. View Article : Google Scholar : PubMed/NCBI
13	Zhu W, Hu H, Qiu P and Yan G: Triptolide induces apoptosis in human anaplastic thyroid carcinoma cells by a p53-independent but NF-kappaB-related mechanism. Oncol Rep. 22:1397–1401. 2009.PubMed/NCBI
14	Li H, Takai N, Yuge A, et al: Novel target genes responsive to the anti-growth activity of triptolide in endometrial and ovarian cancer cells. Cancer Lett. 297:198–206. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kim MJ, Lee TH, Kim SH, Choi YJ, Heo J and Kim YH: Triptolide inactivates Akt and induces caspase-dependent death in cervical cancer cells via the mitochondrial pathway. Int J Oncol. 37:1177–1185. 2010.PubMed/NCBI
16	Wu PP, Liu KC, Huang WW, et al: Triptolide induces apoptosis in human adrenal cancer NCI-H295 cells through a mitochondrial-dependent pathway. Oncol Rep. 25:551–557. 2011.PubMed/NCBI
17	Antonoff MB, Chugh R, Borja-Cacho D, et al: Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery. 146:282–290. 2009. View Article : Google Scholar : PubMed/NCBI
18	Lee KY, Park JS, Jee YK and Rosen GD: Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation. Exp Mol Med. 34:462–468. 2002. View Article : Google Scholar : PubMed/NCBI
19	Morgan MJ and Liu ZG: Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 21:103–115. 2011. View Article : Google Scholar : PubMed/NCBI
20	Kane DJ, Sarafian TA, Anton R, et al: Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 262:1274–1277. 1993. View Article : Google Scholar : PubMed/NCBI
21	Liu GH, Wang SR, Wang B and Kong BH: Inhibition of nuclear factor-kappaB by an antioxidant enhances paclitaxel sensitivity in ovarian carcinoma cell line. Int J Gynecol Cancer. 16:1777–1782. 2006. View Article : Google Scholar : PubMed/NCBI
22	Cohen GM: Caspases: the executioners of apoptosis. Biochem J. 326:1–16. 1997.
23	Riedl SJ and Shi Y: Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 5:897–907. 2004. View Article : Google Scholar : PubMed/NCBI
24	Fang J, Nakamura H and Iyer AK: Tumor-targeted induction of oxystress for cancer therapy. J Drug Target. 15:475–486. 2007. View Article : Google Scholar : PubMed/NCBI
25	Adam-Vizi V and Chinopoulos C: Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci. 27:639–645. 2006. View Article : Google Scholar : PubMed/NCBI
26	Silasi DA, Alvero AB, Rutherford TJ, Brown D and Mor G: Phenoxodiol: pharmacology and clinical experience in cancer monotherapy and in combination with chemotherapeutic drugs. Expert Opin Pharmacother. 10:1059–1067. 2009. View Article : Google Scholar : PubMed/NCBI
27	Sung B, Kunnumakkara AB, Sethi G, Anand P, Guha S and Aggarwal BB: Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol Cancer Ther. 8:959–970. 2009. View Article : Google Scholar : PubMed/NCBI
28	Yang YI, Kim JH, Lee KT and Choi JH: Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species. Gynecol Oncol. 123:588–596. 2011. View Article : Google Scholar : PubMed/NCBI
29	Berkenblit A and Cannistra SA: Advances in the management of epithelial ovarian cancer. J Reprod Med. 50:426–438. 2005.
30	Yang M, Huang J, Pan HZ and Jin J: Triptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/NF-kappaB pathways in human multiple myeloma cells. Int J Mol Med. 22:489–496. 2008.PubMed/NCBI
31	Chen YW, Lin GJ, Chuang YP, et al: Triptolide circumvents drug-resistant effect and enhances 5-fluorouracil antitumor effect on KB cells. Anticancer Drugs. 21:502–513. 2010. View Article : Google Scholar : PubMed/NCBI
32	Hampton MB and Orrenius S: Redox regulation of apoptotic cell death. Biofactors. 8:1–5. 1998. View Article : Google Scholar : PubMed/NCBI
33	Toyokuni S, Okamoto K, Yodoi J and Hiai H: Persistent oxidative stress in cancer. FEBS Lett. 358:1–3. 1995. View Article : Google Scholar
34	Fruehauf JP and Meyskens FL Jr: Reactive oxygen species: a breath of life or death? Clin Cancer Res. 13:789–794. 2007. View Article : Google Scholar : PubMed/NCBI
35	Maiti AK: Genetic determinants of oxidative stress-mediated sensitization of drug-resistant cancer cells. Int J Cancer. 130:1–9. 2012. View Article : Google Scholar : PubMed/NCBI
36	Kurosu T, Fukuda T, Miki T and Miura O: BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. Oncogene. 22:4459–4468. 2003. View Article : Google Scholar : PubMed/NCBI
37	Maiti AK: Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells. Pharmacogenomics J. 10:94–104. 2010. View Article : Google Scholar : PubMed/NCBI
38	Xu B, Guo X, Mathew S, et al: Triptolide simultaneously induces reactive oxygen species, inhibits NF-kappaB activity and sensitizes 5-fluorouracil in colorectal cancer cell lines. Cancer Lett. 291:200–208. 2010. View Article : Google Scholar : PubMed/NCBI
39	Bao X, Cui J, Wu Y, et al: The roles of endogenous reactive oxygen species and nitric oxide in triptolide-induced apoptotic cell death in macrophages. J Mol Med (Berl). 85:85–98. 2007. View Article : Google Scholar : PubMed/NCBI
40	Lau AT, Wang Y and Chiu JF: Reactive oxygen species: current knowledge and applications in cancer research and therapeutic. J Cell Biochem. 104:657–667. 2008. View Article : Google Scholar : PubMed/NCBI
41	Engel RH and Evens AM: Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front Biosci. 11:300–312. 2006. View Article : Google Scholar : PubMed/NCBI
42	Dias N and Bailly C: Drugs targeting mitochondrial functions to control tumor cell growth. Biochem Pharmacol. 70:1–12. 2005. View Article : Google Scholar : PubMed/NCBI
43	Chen G, Zhang X, Zhao M, et al: Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells. BMC Cancer. 11:1702011. View Article : Google Scholar
44	Mabuchi S, Ohmichi M, Nishio Y, et al: Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. J Biol Chem. 279:23477–23485. 2004. View Article : Google Scholar : PubMed/NCBI
45	Park B, Sung B, Yadav VR, Chaturvedi MM and Aggarwal BB: Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway. Biochem Pharmacol. 82:1134–1144. 2011. View Article : Google Scholar
46	Wang J, Zhou JY, Zhang L and Wu GS: Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells. Cell Cycle. 8:3191–3198. 2009. View Article : Google Scholar : PubMed/NCBI
47	Mansouri A, Zhang Q, Ridgway LD, Tian L and Claret FX: Cisplatin resistance in an ovarian carcinoma is associated with a defect in programmed cell death control through XIAP regulation. Oncol Res. 13:399–404. 2003.PubMed/NCBI
48	Schreck R, Rieber P and Baeuerle PA: Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 10:2247–2258. 1991.PubMed/NCBI
49	Van Waes C: Nuclear factor-kappaB in development, prevention, and therapy of cancer. Clin Cancer Res. 13:1076–1082. 2007.PubMed/NCBI
50	Korn SH, Wouters EF, Vos N and Janssen-Heininger YM: Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase. J Biol Chem. 276:35693–35700. 2001. View Article : Google Scholar : PubMed/NCBI
51	Kapahi P, Takahashi T, Natoli G, et al: Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem. 275:36062–36066. 2000. View Article : Google Scholar : PubMed/NCBI