Erastin/sorafenib induces cisplatin‑resistant non‑small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway

Li,Yu; Yan,Hengyi; Xu,Xiaoman; Liu,Hongbo; Wu,Cen; Zhao,Li

doi:10.3892/ol.2019.11066

Erastin/sorafenib induces cisplatin‑resistant non‑small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway

Authors:
- Yu Li
- Hengyi Yan
- Xiaoman Xu
- Hongbo Liu
- Cen Wu
- Li Zhao
View Affiliations

Affiliations: Department of Respiratory Medicine and Medical Intensive Care Unit, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: November 7, 2019 https://doi.org/10.3892/ol.2019.11066
Pages: 323-333
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Non‑small cell lung cancer (NSCLC) has long been one of the most lethal types of cancer due to its lack of typical clinical symptoms at early stages and high risk of tumour recurrence, even following complete surgical resection. Multicourse chemotherapy based on cisplatin (CDDP) is the standard adjuvant treatment for NSCLC; however, its benefits for the overall survival of patients are limited. In this study, NSCLC cells possessing CDDP‑resistant characteristics (N5CP cells), obtained from surgical resection of clinical specimens of patients with NSCLC, were cultured and screened to generate research models. This study aimed to identify the mechanism underlying tumour cell resistance to CDDP and to identify a novel treatment for NSCLC following CDDP failure. CDDP‑mediated NF‑E2 related factor 2 (Nrf2)/light chain of System xc‑ (xCT) pathway activation was associated with the resistance of cells to CDDP. Therefore, erastin/sorafenib regulation of Nrf2 or xCT expression may alter the sensitivity of tumour cells to CDDP. The small molecules erastin and sorafenib effectively induced N5CP cell ferroptosis, which was mediated by the accumulation of intracellular lipid reactive oxygen species. Additionally, low doses of erastin or sorafenib could be used in association with CDDP to effectively trigger N5CP cell ferroptosis. Furthermore, it was indicated that erastin and sorafenib, alone or in combination with a low dose of CDDP, effectively inhibited the growth of N5CP cells in vivo. Therefore, ferroptosis inducers, including erastin and sorafenib, may be considered a novel treatment regimen for patients with NSCLC, particularly patients with CDDP failure.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
3	Casiraghi M, Maisonneuve P, Piperno G, Bellini R, Brambilla D, Petrella F, Marinis F and Spaggiari L: Salvage surgery after definitive chemoradiotherapy for non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 29:233–241. 2017. View Article : Google Scholar : PubMed/NCBI
4	Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D and Bray F: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 49:1374–1403. 2013. View Article : Google Scholar : PubMed/NCBI
5	Tiseo M, Franciosi V, Grossi F and Ardizzoni A: Adjuvant chemotherapy for non-small cell lung cancer: Ready for clinical practice? Eur J Cancer. 42:8–16. 2006. View Article : Google Scholar : PubMed/NCBI
6	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
7	Roh JL, Kim EH, Jang HJ, Park JY and Shin D: Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 381:96–103. 2016. View Article : Google Scholar : PubMed/NCBI
8	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
9	Kaminskyy VO, Piskunova T, Zborovskaya IB, Tchevkina EM and Zhivotovsky B: Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation. Autophagy. 8:1032–1044. 2012. View Article : Google Scholar : PubMed/NCBI
10	Tian Y, Wu K, Liu Q, Han N, Zhang L, Chu Q and Chen Y: Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer. J Hematol Oncol. 9:832016. View Article : Google Scholar : PubMed/NCBI
11	Hou X, Bai X, Gou X, Zeng H, Xia C, Zhuang W, Chen X, Zhao Z, Huang M and Jin J: 3′,4′,5′,5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway. Mol Cells. 38:396–401. 2015. View Article : Google Scholar : PubMed/NCBI
12	Ansari MA: Sinapic acid modulates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother. 93:646–653. 2017. View Article : Google Scholar : PubMed/NCBI
13	Zhang P, Wang W, Wei Z, Xu LI, Yang X and Du Y: xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells. Oncol Lett. 12:307–314. 2016. View Article : Google Scholar : PubMed/NCBI
14	Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C and Itoh K: Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol. 34:3421–3434. 2014. View Article : Google Scholar : PubMed/NCBI
15	Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, Chauffert B and Galmiche A: Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 34:6417–6422. 2014.PubMed/NCBI
16	Pillai MM, Elakkiya V, Gopinathan J, Sabarinath C, Shanthakumari S, Sahanand KS, Dinakar Rai BK, Bhattacharyya A and Selvakumar R: A combination of biomolecules enhances expression of E-cadherin and peroxisome proliferator-activated receptor gene leading to increased cell proliferation in primary human meniscal cells: An in vitro study. Cytotechnology. 68:1747–1761. 2016. View Article : Google Scholar : PubMed/NCBI
17	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
18	Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, et al: Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res. 15:3423–3432. 2009. View Article : Google Scholar : PubMed/NCBI
19	Namani A, Cui QQ, Wu Y, Wang H, Wang XJ and Tang X: NRF2-regulated metabolic gene signature as a prognostic biomarker in non-small cell lung cancer. Oncotarget. 8:69847–69862. 2017. View Article : Google Scholar : PubMed/NCBI
20	Chen D, Fan Z, Rauh M, Buchfelder M, Eyupoglu IY and Savaskan N: ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene. 36:5593–5608. 2017. View Article : Google Scholar : PubMed/NCBI
21	Gao M, Monian P, Pan Q, Zhang W, Xiang J and Jiang X: Ferroptosis is an autophagic cell death process. Cell Res. 26:1021–1032. 2016. View Article : Google Scholar : PubMed/NCBI
22	Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R and Tang D: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 63:173–184. 2016. View Article : Google Scholar : PubMed/NCBI
23	Gao M, Monian P, Quadri N, Ramasamy R and Jiang X: Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 59:298–308. 2015. View Article : Google Scholar : PubMed/NCBI
24	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
25	Hamilton G and Rath B: A short update on cancer chemoresistance. Wien Med Wochenschr. 164:456–460. 2014. View Article : Google Scholar : PubMed/NCBI
26	Friedman R: Drug resistance in cancer: Molecular evolution and compensatory proliferation. Oncotarget. 7:11746–11755. 2016. View Article : Google Scholar : PubMed/NCBI
27	Batra A, Thakar A and Bakhshi S: Ototoxicity in retinoblastoma survivors treated with carboplatin based chemotherapy: A cross-sectional study of 116 patients. Pediatr Blood Cancer. 62:20602015. View Article : Google Scholar : PubMed/NCBI
28	Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, et al: Crizotinib versus chemotherapy in asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 50:691–700. 2018. View Article : Google Scholar : PubMed/NCBI
29	Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI
30	Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, et al: Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 16:1180–1191. 2014. View Article : Google Scholar : PubMed/NCBI
31	Latunde-Dada GO: Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 1861:1893–1900. 2017. View Article : Google Scholar : PubMed/NCBI
32	Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, et al: Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 171:273–285. 2017. View Article : Google Scholar : PubMed/NCBI
33	Macrez R, Stys PK, Vivien D, Lipton SA and Docagne F: Mechanisms of glutamate toxicity in multiple sclerosis: Biomarker and therapeutic opportunities. Lancet Neurol. 15:1089–1102. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zenlea T and Peppercorn MA: Immunosuppressive therapies for inflammatory bowel disease. World J Gastroenterol. 20:3146–3152. 2014. View Article : Google Scholar : PubMed/NCBI
35	Ma MZ, Chen G, Wang P, Lu WH, Zhu CF, Song M, Yang J, Wen S, Xu RH, Hu Y and Huang P: Xc- inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism. Cancer Lett. 368:88–96. 2015. View Article : Google Scholar : PubMed/NCBI
36	Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y, et al: Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer. 20:1004–1009. 2017. View Article : Google Scholar : PubMed/NCBI
37	Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM and Lynch M: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 7:3129–3140. 2008. View Article : Google Scholar : PubMed/NCBI
38	Rushmore TH, Morton MR and Pickett CB: The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 266:11632–11639. 1991.PubMed/NCBI
39	Hayes JD and McMahon M: Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett. 174:103–113. 2001. View Article : Google Scholar : PubMed/NCBI
40	Chang LC, Chiang SK, Chen SE, Yu YL, Chou RH and Chang WC: Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis. Cancer Lett. 416:124–137. 2018. View Article : Google Scholar : PubMed/NCBI
41	Houessinon A, Francois C, Sauzay C, Louandre C, Mongelard G, Godin C, Bodeau S, Takahashi S, Saidak Z, Gutierrez L, et al: Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib. Mol Cancer. 15:382016. View Article : Google Scholar : PubMed/NCBI
42	Sun H, Zhu J, Lin H, Gu K and Feng F: Recent progress in the development of small molecule Nrf2 modulators: A patent review (2012–2016). Expert Opin Ther Pat. 27:763–785. 2017. View Article : Google Scholar : PubMed/NCBI