Anticancer effect of exogenous hydrogen sulfide in cisplatin‑resistant A549/DDP cells

Ma,Ying; Yan,Zhonghai; Deng,Xiaomei; Guo,Junqi; Hu,Jinxia; Yu,Yuan; Jiao,Fei

doi:10.3892/or.2018.6362

Anticancer effect of exogenous hydrogen sulfide in cisplatin‑resistant A549/DDP cells

Authors:
- Ying Ma
- Zhonghai Yan
- Xiaomei Deng
- Junqi Guo
- Jinxia Hu
- Yuan Yu
- Fei Jiao
View Affiliations

Affiliations: Department of Biochemistry and Molecular Biology, Binzhou Medical College, Yantai, Shandong 264003, P.R. China, Department of Medicine, College of Physicians and Surgeons, Columbia University New York, NY 10032, USA, Yantai Blood Center, Yantai, Shandong 264003, P.R. China
Published online on: April 12, 2018 https://doi.org/10.3892/or.2018.6362
Pages: 2969-2977

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

Despite huge advances in lung cancer treatment, resistance to cisplatin‑based chemotherapy remains one of the major obstacles, and the elucidation of cisplatin resistance remains challenging. As an important biological and pharmacological mediator, hydrogen sulfide (H2S) performs a variety of homeostatic functions related to cancer formation and development. However, the effects of H2S on cisplatin‑resistance lung cancer remain largely unknown. In the present study, we investigated the anticancer effects and relevant mechanisms of NaHS (an exogenous donor of H2S) on A549/DDP cells (cisplatin‑resistant). The intracellular H2S was first evaluated using a fluorescence probe in A549 (cisplatin‑sensitive) and A549/DDP cells. We found that H2S production was markedly decreased in A549/DDP cells compared with that in A549 cells, accomplished by the downregulation of cystathionine β‑synthase (CBS), an endogenous H2S‑producing enzyme. In view of these findings, we then observed the effects of NaHS treatment on A549/DDP cells. The results showed that NaHS exposure exhibited an inhibitory effect on cell viability and the IC50 of cisplatin in A549/DDP cells decreased markedly during NaHS treatment (800 µmol/l). In addition, our data revealed that NaHS treatment of A549/DDP cells resulted in the induction of apoptosis, cell cycle arrest and inhibition of cell migration and invasion. Finally, we demonstrated that the marked changes in the A549/DDP cell response to NaHS may be triggered by the activation of p53, and overexpression of p21, caspase‑3, Bax and MMP‑2, as well as the downregulation of Bcl‑xL. The findings of the present study provide novel evidence that NaHS administration may represent a new strategy for the treatment of cisplatin‑resistant lung cancer.

View Figures

View References

1	Ma LY, Xie XW, Ma L, Pang JL, Xiong XM, Zheng HD, Shen XL, Wen ZG and Wang HY: Downregulated long non-coding RNA TRPM2-AS inhibits cisplatin resistance of non-small cell lung cancer cells via activation of p53-p66shc pathway. Eur Rev Med Pharmacol Sci. 21:2626–2634. 2017.PubMed/NCBI
2	Gao J, Meng Q, Zhao Y, Chen X and Cai L: EHD1 confers resistance to cisplatin in non-small cell lung cancer by regulating intracellular cisplatin concentrations. BMC Cancer. 16:4702016. View Article : Google Scholar : PubMed/NCBI
3	Fennell DA, Summers Y, Cadranel J, Benepal T, Christoph DC, Lal R, Das M, Maxwell F, Visseren-Grul C and Ferry D: Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev. 44:42–50. 2016. View Article : Google Scholar : PubMed/NCBI
4	Sarin N, Engel F, Kalayda GV, Mannewitz M, Cinatl J Jr, Rothweiler F, Michaelis M, Saafan H, Ritter CA, Jaehde U and Frötschl R: Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS One. 12:e01810812017. View Article : Google Scholar : PubMed/NCBI
5	Rose MC, Kostyanovskaya E and Huang RS: Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer. Genomics Proteomics Bioinformatics. 12:198–209. 2014. View Article : Google Scholar : PubMed/NCBI
6	Hellmich MR, Coletta C, Chao C and Szabo C: The therapeutic potential of cystathionine β-synthetase/hydrogen sulfide inhibition in cancer. Antioxid Redox Signal. 22:424–448. 2015. View Article : Google Scholar : PubMed/NCBI
7	Wu D, Si W, Wang M, Lv S, Ji A and Li Y: Hydrogen sulfide in cancer: Friend or foe? Nitric Oxide. 50:38–45. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wallace JL and Wang R: Hydrogen sulfide-based therapeutics: Exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov. 14:329–345. 2015. View Article : Google Scholar : PubMed/NCBI
9	Rose P, Moore PK and Zhu YZ: H2S biosynthesis and catabolism: New insights from molecular studies. Cell Mol Life Sci. 74:1391–1412. 2017. View Article : Google Scholar : PubMed/NCBI
10	Szabo C: Gasotransmitters in cancer: From pathophysiology to experimental therapy. Nat Rev Drug Discov. 15:185–203. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhao Y, Biggs TD and Xian M: Hydrogen sulfide (H₂S) releasing agents: Chemistry and biological applications. Chem Commun. 50:11788–11805. 2014. View Article : Google Scholar
12	Guo FF, Yu TC, Hong J and Fang JY: Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases. Front Physiol. 7:1562016. View Article : Google Scholar : PubMed/NCBI
13	Lee ZW, Teo XY, Tay EY, Tan CH, Hagen T, Moore PK and Deng LW: Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance. Br J Pharmacol. 171:4322–4336. 2014. View Article : Google Scholar : PubMed/NCBI
14	Szabo C, Coletta C, Chao C, Módis K, Szczesny B, Papapetropoulos A and Hellmich MR: Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA. 110:12474–12479. 2013. View Article : Google Scholar : PubMed/NCBI
15	Bhattacharyya S, Saha S, Giri K, Lanza IR, Nair KS, Jennings NB, Rodriguez-Aguayo C, Lopez-Berestein G, Basal E, Weaver AL, et al: Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance. PLoS One. 8:e791672013. View Article : Google Scholar : PubMed/NCBI
16	Szczesny B, Marcatti M, Zatarain JR, Druzhyna N, Wiktorowicz JE, Nagy P, Hellmich MR and Szabo C: Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics. Sci Rep. 6:361252016. View Article : Google Scholar : PubMed/NCBI
17	Russo A, Saide A, Cagliani R, Cantile M, Botti G and Russo G: RpL3 promotes the apoptosis of p53 mutated lung cancer cells by down-regulating CBS and NF-κB upon 5-FU treatment. Sci Rep. 6:383692016. View Article : Google Scholar : PubMed/NCBI
18	Wang R, Yu FB, Chen LX, Chen H, Wang LJ and Zhang WW: A highly selective turn-on near-infrared fluorescent probe for hydrogen sulfide detection and imaging in living cells. Chem Commun. 48:11757–11759. 2012. View Article : Google Scholar
19	Zhao L, Wang Y, Yan Q, Lv W, Zhang Y and He S: Exogenous hydrogen sulfide exhibits anti-cancer effects though p38 MAPK signaling pathway in C6 glioma cells. Biol Chem. 396:1247–1253. 2015. View Article : Google Scholar : PubMed/NCBI
20	Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK and Deng LW: The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS One. 6:e210772011. View Article : Google Scholar : PubMed/NCBI
21	Chen Y, Gao Y, Zhang K, Li C, Pan Y, Chen J, Wang R and Chen L: MicroRNAs as regulators of cisplatin resistance in lung cancer. Cell Physiol Biochem. 37:1869–1880. 2015. View Article : Google Scholar : PubMed/NCBI
22	Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M and Kroemer G: Systems biology of cisplatin resistance: Past, present and future. Cell Death Dis. 5:e12572014. View Article : Google Scholar : PubMed/NCBI
23	Chattopadhyay M, Kodela R, Nath N, Dastagirzada YM, Velázquez-Martínez CA, Boring D and Kashfi K: Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: A general property and evidence of a tissue type-independent effect. Biochem Pharmacol. 83:715–722. 2012. View Article : Google Scholar : PubMed/NCBI
24	Wu YC, Wang XJ, Yu L, Chan FK, Cheng AS, Yu J, Sung JJ, Wu WK and Cho CH: Hydrogen sulfide lowers proliferation and induces protective autophagy in colon epithelial cells. PLoS One. 7:e375722012. View Article : Google Scholar : PubMed/NCBI
25	Lv M, Li Y, Ji MH, Zhuang M and Tang JH: Inhibition of invasion and epithelial-mesenchymal transition of human breast cancer cells by hydrogen sulfide through decreased phospho-p38 expression. Mol Med Rep. 10:341–346. 2014. View Article : Google Scholar : PubMed/NCBI
26	De Preter G, Deriemaeker C, Danhier P, Brisson L, Pham Cao TT, Grégoire V, Jordan BF, Sonveaux P and Gallez B: A fast hydrogen sulfide-releasing donor increases the tumor response to radiotherapy. Mol Cancer Ther. 15:154–161. 2016. View Article : Google Scholar : PubMed/NCBI
27	Liu M, Wu L, Montaut S and Yang G: Hydrogen sulfide signaling axis as a target for prostate cancer therapeutics. Prostate Cancer. 2016:81085492016. View Article : Google Scholar : PubMed/NCBI
28	Wu D, Li M, Tian W, Wang S, Cui L, Li H, Wang H, Ji A and Li Y: Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Sci Rep. 7:51342017. View Article : Google Scholar : PubMed/NCBI
29	Hientz K, Mohr A, Bhakta-Guha D and Efferth T: The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget. 8:8921–8946. 2017. View Article : Google Scholar : PubMed/NCBI
30	Pflaum J, Schlosser S and Müller M: p53 family and cellular stress responses in cancer. Front Oncol. 4:2852014. View Article : Google Scholar : PubMed/NCBI
31	Lane D and Levine A: p53 research: The past thirty years and the next thirty years. Cold Spring Harb Perspect Bio. 2:a0008932010.
32	Davaadelger B, Duan L, Perez RE, Gitelis S and Maki CG: Crosstalk between the IGF-1R/AKT/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor. Oncotarget. 7:27511–27526. 2016. View Article : Google Scholar : PubMed/NCBI
33	Leung EL, Fraser M, Fiscus RR and Tsang BK: Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: Involvement in p53 regulation and cisplatin resistance. Br J Cancer. 98:1803–1809. 2008. View Article : Google Scholar : PubMed/NCBI
34	Häcker S, Karl S, Mader I, Cristofanon S, Schweitzer T, Krauss J, Rutkowski S, Debatin KM and Fulda S: Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation. Oncogene. 30:2275–2281. 2011. View Article : Google Scholar : PubMed/NCBI
35	Gregorc V, Ludovini V, Pistola L, Darwish S, Floriani I, Bellezza G, Sidoni A, Cavaliere A, Scheibel M, De Angelis V, et al: Relevance of p53, bcl-2 and Rb expression on resistance to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 39:41–48. 2003. View Article : Google Scholar : PubMed/NCBI
36	Zhang L, Qi Q, Yang J, Sun D, Li C, Xue Y, Jiang Q, Tian Y, Xu C and Wang R: An anticancer role of hydrogen sulfide in human gastric cancer cells. Oxid Med Cell Longev. 2015:6364102015. View Article : Google Scholar : PubMed/NCBI
37	Guo W, Cheng ZY and Zhu YZ: Hydrogen sulfide and translational medicine. Acta Pharmacol Sin. 34:1284–1291. 2013. View Article : Google Scholar : PubMed/NCBI