Open Access

Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways

  • Authors:
    • Hao Wang
    • Ying‑Hua Luo
    • Gui‑Nan Shen
    • Xian‑Ji Piao
    • Wan‑Ting Xu
    • Yi Zhang
    • Jia‑Ru Wang
    • Yu‑Chao Feng
    • Jin‑Qian Li
    • Yu Zhang
    • Tong Zhang
    • Shi‑Nong Wang
    • Hui Xue
    • Hong‑Xing Wang
    • Chang‑Yuan Wang
    • Cheng‑Hao Jin
  • View Affiliations

  • Published online on: July 15, 2019     https://doi.org/10.3892/mmr.2019.10500
  • Pages: 2571-2582
  • Copyright: © Wang 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: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

1,4‑Naphthoquinone derivatives have superior anticancer effects, but their use has been severely limited in clinical practice due to adverse side effects. To reduce the side effects and extend the anticancer effects of 1,4‑naphthoquinone derivatives, 2‑(butane‑1‑sulfinyl)‑1,4‑naphthoquinone (BQ) and 2‑(octane‑1‑sulfinyl)‑1,4‑naphthoquinone (OQ) were synthesized, and their anticancer activities were investigated. The anti‑proliferation effects, determined by MTT assays, showed that BQ and OQ significantly inhibited the viability of gastric cancer cells and had no significant cytotoxic effect on normal cell lines. The apoptotic effect was determined by flow cytometry, and the results showed that BQ and OQ induced cell apoptosis by regulating the mitochondrial pathway and cell cycle arrest at the G2/M phase via inhibition of the Akt signaling pathway in AGS cells. Furthermore, BQ and OQ significantly increased the levels of reactive oxygen species (ROS) and this effect was blocked by the ROS scavenger NAC in AGS cells. BQ and OQ induced apoptosis by upregulating the protein expression of p38 and JNK and downregulating the levels of ERK and STAT3. Furthermore, expression levels of these proteins were also blocked after NAC treatment. These results demonstrated that BQ and OQ induced apoptosis and cell cycle arrest at the G2/M phase in AGS cells by stimulating ROS generation, which caused subsequent activation of MAPK, Akt and STAT3 signaling pathways. Thus, BQ and OQ may serve as potential therapeutic agents for the treatment of human gastric cancer.

References

1 

Jou E and Rajdev L: Current and emerging therapies in unresectable and recurrent gastric cancer. World J Gastroenterol. 20:4812–4823. 2016. View Article : Google Scholar

2 

Lee SY and Oh SC: Changing strategies for target therapy in gastric cancer. World J Gastroenterol. 3:1179–1189. 2016. View Article : Google Scholar

3 

Han G, Gong H, Wang Y, Guo S and Liu K: AMPK/mTOR-mediated inhibition of surviving partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther. 16:77–87. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Zhang C, Chen Z, Zhou X, Xu W, Wang G, Tang X, Luo L, Tu J, Zhu Y, Hu W, et al: Cantharidin induces G2/M phase arrest and apoptosis in human gastric cancer SGC-7901 and BGC-823 cells. Oncol Lett. 6:2721–2726. 2014. View Article : Google Scholar

5 

Sinha K, Das J, Pal PB and Sil PC: Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 87:1157–1180. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Woo SM, Choi YK, Kim AJ, Cho SG and Ko SG: p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells. Mol Med Rep. 13:1091–1096. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Lan Q, Li S, Lai W, Xu H, Zhang Y, Zeng Y, Lan W and Chu Z: Methyl sartortuoate inhibits colon cancer cell growth by inducing apoptosis and G2/M-phase arrest. Int J Mol Sci. 16:19401–194118. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Lee H, Lee H, Chin H, Kim K and Lee D: ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells. Oncotarget. 5:5138–5152. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Yang L, Zhou Y, Li Y, Zhou J, Wu Y, Cui Y, Yang G and Hong Y: Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Lett. 357:520–526. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Kumar K, Sabarwal A and Singh RP: Mancozeb selectively induces mitochondrial-mediated apoptosis in human gastric carcinoma cells through ROS generation. Mitochondrion. Jun 11–2018.(Epub ahead of print). View Article : Google Scholar :

11 

Duan F, Yu Y, Guan R, Xu Z, Liang H and Hong L: Vitamin K2 induces mitochondria-related apoptosis in human bladder cancer cells via ROS and JNK/p38 MAPK signal pathways. PLoS One. 11:e01618862016. View Article : Google Scholar : PubMed/NCBI

12 

Cheng HB, Bo Y, Shen WX, Ren XG, Tan JN, Jia ZR and Xu CL: Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS. Naunyn Schmiedebergs Arch Pharmacol. 388:623–634. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Rajamanickam V, Zhu H, Feng C, Chen X, Zheng H, Xu X, Zhang Q, Zou P, He G, Dai X, et al: Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3. Oncotarget. 8:101112–101129. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Zhang Q, Dong J, Cui J, Huang G, Meng Q and Li S: Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime derivatives on selected human cancer cell lines. Chem Pharm Bull (Tokyo). 66:612–619. 2018. View Article : Google Scholar : PubMed/NCBI

15 

Ghosh SK, Ganta A and Spanjaard RA: Discovery and cellular stress pathway analysis of 1,4-naphthoquinone derivatives with novel, highly potent broad-spectrum anticancer activity. J Biomed Sci. 25:122018. View Article : Google Scholar : PubMed/NCBI

16 

Farias MS, Pich CT, Kviecinski MR, Bucker NC, Felipe KB, Da Silva FO, Günther TM, Correia JF, Ríos D, Benites J, et al: Substituted 3-acyl-2-2-phenylamino-1,4-naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death. Mol Med Rep. 10:405–410. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Ollinger K and Brunmark A: Effect of hydroxy substituentposition on 1,4-naphthoquinone toxicity to rat hepatocyt. J Biol Chem. 266:21496–22150. 1991.PubMed/NCBI

18 

Ball MD, Bartlett MS, Shaw M, Smith JW, Nasr M and Meshnick SR: Activities and conformational fitting of 1,4-Naphthoquinone Derivatives and other cyclic 1,4-Diones tested in vitro against Pneumocystis carinii. Antimicrob Agents Chemother. 45:1473–1479. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Suhara Y, Watanabe M, Motoyoshi S, Nakagawa K, Wada A, Takeda K, Takahashi K, Tokiwa H and Okano T: Synthesis of new vitamin K analogues as steroid and xenobiotic receptor (SXR) agonists: Insights into the biological role of the side chain part of vitamin K. J Med Chem. 54:4918–4922. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Abiko Y, Shinkai Y, Unoki T, Hirose R, Uehara T and Kumagai Y: Polysulfide Na2S4 regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts. Sci Rep. 7:48142017. View Article : Google Scholar : PubMed/NCBI

21 

Bezkorovaynyj AO, Zyn AR, Harasym NM, Len JT, Figurka OM and Figurka DI: Loach embryos prooxidant-antioxidant status under the influence of amide derivatives of 1,4-naphthoquinone. Ukr Biochem J. 88:46–53. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Oh B, Figtree G, Costa D, Eade T, Hruby G, Lim S, Elfiky A, Martine N, Rosenthal D, Clarke S and Back M: Oxidative stress in prostate cancer patients: A systematic review of case control studies. Prostate Int. 4:71–87. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Zhang L, Zheng YX, Deng HZ, Liang L and Peng J: Aloperine induces G2/M phase cell cycle arrest and apoptosis in HCT116 human colon cancer cells. Int J Mol Med. 33:1613–1620. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Ma WD, Zou YP, Wang P, Yao XH, Sun Y, Duan MH, Fu YJ and Yu B: Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS-mediated mitochondrial pathway. Food Chem Toxicol. 70:1–8. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Ong JY, Yong PV, Lim YM and Ho AS: 2-Methoxy-1, 4-naphthoquinone (MNQ) induces apoptosis of A549 lung adenocarcinoma cells via oxidation-triggered JNK and p38 MAPK signaling pathways. Life Sci. 135:158–164. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Eldhose B, Gunawan M, Rahman M, Latha MS and Notario V: Plumbagin reduces human colon cancer cell survival by inducing cell cycle arrest and mitochondria-mediated apoptosis. Int J Oncol. 45:1913–1920. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Zhang YL, Zhang R, Xu HL, Yu XF, Qu SC and Sui DY: 20(S)-protopanaxadiol triggers mitochondrial-mediated apoptosis in human lung adenocarcinoma A549 cells via inhibiting the PI3K/Akt signaling pathway. Am J Chin Med. 41:1137–1152. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Laux I and Nel A: Evidence that oxidative stress-induced apoptosis by menadione involves Fas-dependent and Fas-independent pathways. Clin Immunol. 101:335–344. 2001. View Article : Google Scholar : PubMed/NCBI

29 

McKallip RJ, Lombard C, Sun J and Ramakrishnan R: Plumbagin-induced apoptosis in lymphocytes is mediated through increased reactive oxygen species production, upregulation of Fas, and activation of the caspase cascade. Toxicol Appl Pharmacol. 247:41–52. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Tian R, Li Y and Gao M: Shikonin causes cell-cycle arrest and induces apoptosis by regulating the EGFR-NF-κB signalling pathway in human epidermoid carcinoma A431 cells. Biosci Rep. 35(pii): e001892015.PubMed/NCBI

31 

Xu N, Lao Y, Zhang Y and Gillespie DA: Akt: A double-edged sword in cell proliferation and genome stability. J Oncol. 2012:9517242012. View Article : Google Scholar : PubMed/NCBI

32 

Shan ZL, Zhong L, Xiao CL, Gan LG, Xu T, Song H, Yang R, Li L and Liu BZ: Shikonin suppresses proliferation and induces apoptosis in human leukemia NB4 cells through modulation of MAPKs and c-Myc. Mol Med Rep. 16:3055–3060. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Yang J, Zhang JN, Chen WL, Wang GS, Mao Q, Li SQ, Xiong WH, Lin YY, Ge JW, Li XX, et al: Effects of AQP5 gene silencing on proliferation, migration and apoptosis of human glioma cells through regulating EGFR/ERK/p38 MAPK signaling pathway. Oncotarget. 8:38444–38455. 2017.PubMed/NCBI

34 

Tan BB, Zhang MM, Li Y, Zhao Q, Fan LQ, Liu Y and Wang D: Inhibition of Vav3 gene can promote apoptosis of human gastric cancer cell line MGC803 by regulating ERK pathway. Tumour Biol. 37:7823–7833. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Yuan Z, Guo W, Yang J, Li L, Wang M, Lei Y, Wan Y, Zhao X, Luo N, Cheng P, et al: PNAS-4, an Early DNA damage response gene, induces S phase arrest and apoptosis by activating checkpoint kinases in lung cancer cells. J Biol Chem. 290:14927–14944. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Cao Y, Yin X, Jia Y, Liu B, Wu S and Shang M: Plumbagin, a natural naphthoquinone, inhibits the growth of esophageal squamous cell carcinoma cells through inactivation of STAT3. Int J Mol Med. 42:1569–1576. 2018.PubMed/NCBI

37 

Zhong WF, Wang XH, Pan B, Li F, Kuang L and Su ZX: Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways. Oncol Lett. 12:2894–2899. 2016. View Article : Google Scholar : PubMed/NCBI

38 

Verrax J, Delvaux M, Beghein N, Taper H, Gallez B and Buc Calderon P: Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study. Free Radic Res. 39:649–657. 2005. View Article : Google Scholar : PubMed/NCBI

39 

Prachayasittikul V, Pingaew R, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S and Prachayasittikul V: Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives. Eur J Med Chem. 84:247–263. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, H., Luo, Y., Shen, G., Piao, X., Xu, W., Zhang, Y. ... Jin, C. (2019). Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways. Molecular Medicine Reports, 20, 2571-2582. https://doi.org/10.3892/mmr.2019.10500
MLA
Wang, H., Luo, Y., Shen, G., Piao, X., Xu, W., Zhang, Y., Wang, J., Feng, Y., Li, J., Zhang, Y., Zhang, T., Wang, S., Xue, H., Wang, H., Wang, C., Jin, C."Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways". Molecular Medicine Reports 20.3 (2019): 2571-2582.
Chicago
Wang, H., Luo, Y., Shen, G., Piao, X., Xu, W., Zhang, Y., Wang, J., Feng, Y., Li, J., Zhang, Y., Zhang, T., Wang, S., Xue, H., Wang, H., Wang, C., Jin, C."Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways". Molecular Medicine Reports 20, no. 3 (2019): 2571-2582. https://doi.org/10.3892/mmr.2019.10500