Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells

Wang,Yue; Luo,Ying‑Hua; Piao,Xian‑Ji; Shen,Gui‑Nan; Meng,Ling‑Qi; Zhang,Yi; Wang,Jia‑Ru; Li,Jin‑Qian; Wang,Hao; Xu,Wan‑Ting; Liu,Yang; Zhang,Yu; Zhang,Tong; Wang,Shi‑Nong; Sun,Hu‑Nan; Han,Ying‑Hao; Jin,Mei‑Hua; Zang,Yan‑Qing; Zhang,Dong‑Jie; Jin,Cheng‑Hao

doi:10.3892/mmr.2018.9785

Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells

Authors:
- Yue Wang
- Ying‑Hua Luo
- Xian‑Ji Piao
- Gui‑Nan Shen
- Ling‑Qi Meng
- Yi Zhang
- Jia‑Ru Wang
- Jin‑Qian Li
- Hao Wang
- Wan‑Ting Xu
- Yang Liu
- Yu Zhang
- Tong Zhang
- Shi‑Nong Wang
- Hu‑Nan Sun
- Ying‑Hao Han
- Mei‑Hua Jin
- Yan‑Qing Zang
- Dong‑Jie Zhang
- Cheng‑Hao Jin
View Affiliations

Affiliations: Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China, Department of Grass Science, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China, Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang 163316, P.R. China, Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
Published online on: December 21, 2018 https://doi.org/10.3892/mmr.2018.9785
Pages: 1654-1664
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: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Derivatives of 1,4‑naphthoquinone have excellent anti‑cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti‑cancer activity, two novel types of 1,4‑naphthoquinone derivatives, 2,3‑dihydro‑2,3‑epoxy‑2‑propylsulfonyl‑5,8‑dimethoxy‑1,4‑naphthoquinone (EPDMNQ) and 2,3‑dihydro‑2,3‑epoxy‑2‑nonylsulfonyl‑5,8‑dimethoxy‑1,4‑naphthoquinone (ENDMNQ) were synthesized and their anti‑tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway‑associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L‑02, normal lung IMR‑90 and stomach GES‑1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N‑acetyl‑L‑cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c‑Jun N‑terminal kinase and downregulating extracellular signal‑regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS‑modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4‑naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer.

View Figures

View References

1	Zhang ZQ, Meng H, Wang N, Liang LN, Liu LN, Lu SM and Luan Y: Serum microRNA 143 and microRNA 215 as potential biomarkers for the diagnosis of chronic hepatitis and hepatocellular carcinoma. Diagn Pathol. 9:1352014. View Article : Google Scholar : PubMed/NCBI
2	Sellam F, Harir N, Khaled MB, Mrabent NM, Salah R, Benchouk A and Diaf M: Delayed diagnosis of pancreatic cancer reported as more common in a population of North African young adults. J Gastrointest Oncol. 6:505–510. 2015.PubMed/NCBI
3	Bruix J, Reig M and Sherman M: Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 150:835–853. 2016. View Article : Google Scholar : PubMed/NCBI
4	Li Q, Zhu LZ, Yang RJ and Zhu X: Cytotoxic activity of anticancer drugs on hepatocellular carcinoma cells in hypoxic-hyponutritional culture. Int Surg. 99:745–752. 2014. View Article : Google Scholar : PubMed/NCBI
5	Loureiro R, Magalhães-Novais S, Mesquita KA, Baldeiras I, Sousa IS, Tavares LC, Barbosa IA, Oliveira PJ and Vega-Naredo I: Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells. Oncotarget. 6:17081–17096. 2015. View Article : Google Scholar : PubMed/NCBI
6	Wang X, Yan Y, Yang L, Li M and Zhong X: Effect of quercetin on the expression of Bcl-2/Bax apoptotic proteins in endometrial cells of lipopolysaccharide-induced-abortion mice. J Tradit Chin Med. 36:737–742. 2016. View Article : Google Scholar : PubMed/NCBI
7	Yang SY, Miah A, Sales KM, Fuller B, Seifalian AM and Winslet M: Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment. Int J Oncol. 38:1695–1702. 2011.PubMed/NCBI
8	Bao H, Guo CG, Qiu PC, Zhang XL, Dong Q and Wang YK: Long non-coding RNA Igf2as controls hepatocellular carcinoma progression through the ERK/MAPK signaling pathway. Oncol Lett. 14:2831–2837. 2017. View Article : Google Scholar : PubMed/NCBI
9	Lu X, Li C, Wang YK, Jiang K and Gai XD: Sorbitol induces apoptosis of human colorectal cancer cells via p38 MAPK signal transduction. Oncol Lett. 7:1992–1996. 2014. View Article : Google Scholar : PubMed/NCBI
10	Giachello CN, Fiumara F, Giacomini C, Corradi A, Milanese C, Ghirardi M, Benfenati F and Montarolo PG: MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity. J Cell Sci. 123:881–893. 2010. View Article : Google Scholar : PubMed/NCBI
11	Pereira L, Igea A, Canovas B, Dolado I and Nebreda AR: Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK. EMBO Mol Med. 5:1759–1774. 2013. View Article : Google Scholar : PubMed/NCBI
12	Qu J, Zhao M, Teng Y, Zhang Y, Hou K, Jiang Y, Yang X, Shang H, Qu X and Liu Y: Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway. Cancer Biol Ther. 12:494–502. 2011. View Article : Google Scholar : PubMed/NCBI
13	Atay O and Skotheim JM: Spatial and temporal signal processing and decision making by MAPK pathways. J Cell Biol. 216:317–330. 2017. View Article : Google Scholar : PubMed/NCBI
14	Gong J, Lv L and Huo J: Roles of F-box proteins in human digestive system tumors (Review). Int J Oncol. 45:2199–2207. 2014. View Article : Google Scholar : PubMed/NCBI
15	Tasaki S, Horiguchi A, Asano T, Ito K, Asano T and Asakura H: Docosahexaenoic acid inhibits the phosphorylation of STAT3 and the growth and invasion of renal cancer cells. Exp Ther Med. 14:1146–1152. 2017. View Article : Google Scholar : PubMed/NCBI
16	Yuan J, Zhang F and Niu R: Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 5:176632015. View Article : Google Scholar : PubMed/NCBI
17	Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Adam A, Torres D, Zhang X, Dobrolecki LE, Wei W, Lewis MT, et al: Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene. 34:1341–1353. 2015. View Article : Google Scholar : PubMed/NCBI
18	Kron KJ, Murison A, Zhou S, Huang V, Yamaguchi TN, Shiah YJ, Fraser M, van der Kwast T, Boutros PC, Bristow RG, et al: TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nat Genet. 49:1336–1345. 2017. View Article : Google Scholar : PubMed/NCBI
19	Lai ZQ, Ip SP, Liao HJ, Lu Z, Xie JH, Su ZR, Chen YL, Xian YF, Leung PS and Lin ZX: Brucein D, a naturally occurring tetracyclic triterpene quassinoid, induces apoptosis in pancreatic cancer through ROS-associated PI3K/Akt signaling pathway. Front Pharmacol. 8:9362017. View Article : Google Scholar : PubMed/NCBI
20	Sengupta D, Mazumdar ZH, Mukherjee A, Sharma D, Halder AK, Basu S and Jha T: Benzamide porphyrins with directly conjugated and distal pyridyl or pyridinium groups substituted to the porphyrin macrocycles: Study of the photosensitising abilities as inducers of apoptosis in cancer cells under photodynamic conditions. J Photochem Photobiol B. 178:228–236. 2017. View Article : Google Scholar : PubMed/NCBI
21	Sun J, Song B, Ye Z and Yuan J: Mitochondria targetable time-gated luminescence probe for singlet oxygen based on a β-diketonate-europium complex. Inorg Chem. 54:11660–11668. 2015. View Article : Google Scholar : PubMed/NCBI
22	Gonzalez AA, Zamora L, Reyes-Martinez C, Salinas-Parra N, Roldan N, Cuevas CA, Figueroa S, Gonzalez-Vergara A and Prieto MC: (Pro)renin receptor activation increases profibrotic markers and fibroblast-like phenotype through MAPK-dependent ROS formation in mouse renal collecting duct cells. Clin Exp Pharmacol Physiol. 44:1134–1144. 2017. View Article : Google Scholar : PubMed/NCBI
23	Liu XM, Peyton KJ and Durante W: Ammonia promotes endothelial cell survival via the heme oxygenase-1-mediated release of carbon monoxide. Free Radic Biol Med. 102:37–46. 2017. View Article : Google Scholar : PubMed/NCBI
24	Guerriero E, Sorice A, Capone F, Napolitano V, Colonna G, Storti G, Castello G and Costantini S: Vitamin C effect on mitoxantrone-induced cytotoxicity in human breast cancer cell lines. PLoS One. 9:e1152872014. View Article : Google Scholar : PubMed/NCBI
25	Coelho-Cerqueira E1, Netz PA, do Canto VP, Pinto AC and Follmer C: Beyond topoisomerase inhibition: Antitumor 1,4-naphthoquinones as potential inhibitors of human monoamine oxidase. Chem Biol Drug Des. 83:401–410. 2014. View Article : Google Scholar : PubMed/NCBI
26	Graciani FS and Ximenes VF: 2-Bromo-1,4-naphthoquinone: A potentially improved substitute of menadione in Apatone™ therapy. Braz J Med Biol Res. 45:701–710. 2012. View Article : Google Scholar : PubMed/NCBI
27	Ju Woo H, Jun DY, Lee JY, Park HS, Woo MH, Park SJ, Kim SC, Yang CH and Kim YH: Anti-inflammatory action of 2-carbomethoxy-2,3-epoxy-3-prenyl-1,4-naphthoquinone (CMEP-NQ) suppresses both the MyD88-dependent and TRIF-dependent pathways of TLR4 signaling in LPS-stimulated RAW264.7 cells. J Ethnopharmacol. 205:103–115. 2017. View Article : Google Scholar : PubMed/NCBI
28	P R KR, Fernandez A, Laila SP, B A, C S S and V S V: Synthesis, spectral characterization, crystal structure, cytotoxicity and apoptosis-Inducing activity of two derivatives of 2-hydroxy-1,4-naphthaquinone. Photodiagnosis Photodyn Ther. 17:250–259. 2017. View Article : Google Scholar : PubMed/NCBI
29	Kawiak A and Lojkowska E: Ramentaceone, a naphthoquinone derived from drosera sp., induces apoptosis by suppressing PI3K/Akt signaling in breast cancer cells. PLoS One. 11:e01477182016. View Article : Google Scholar : PubMed/NCBI
30	Liu C, Shen GN, Luo YH, Piao XJ, Jiang XY, Meng LQ, Wang Y, Zhang Y, Wang JR, Wang H, et al: Novel 1,4-naphthoquinone derivatives induce apoptosis via ROS-mediated p38/MAPK, Akt and STAT3 signaling in human hepatoma Hep3B cells. Int J Biochem Cell Biol. 96:9–19. 2018. View Article : Google Scholar : PubMed/NCBI
31	P1rachayasittikul V, Pivngaew 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
32	Lee JJ, Zhang WY, Yi H, Kim Y, Kim IS, Shen GN, Song GY and Myung CS: Anti-proliferative actions of 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone in vascular smooth muscle cells. Biochem Biophys Res Commun. 411:213–218. 2011. View Article : Google Scholar : PubMed/NCBI
33	Lara LS, Moreira CS, Calvet CM, Lechuga GC, Souza RS, Bourguignon SC, Ferreira VF, Rocha D and Pereira MCS: Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound. Eur J Med Chem. 144:572–581. 2017. View Article : Google Scholar : PubMed/NCBI
34	Kishore N, Binneman B, Mahapatra A, van de Venter M, du Plessis-Stoman D, Boukes G, Houghton P, Marion Meyer JJ and Lall N: Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines. Bioorg Med Chem. 22:5013–5019. 2014. View Article : Google Scholar : PubMed/NCBI
35	Bahman AA, Abaza MSI, Khoushiash SI and Al-Attiyah RJ: Sequence-dependent effect of sorafenib in combination with natural phenolic compounds on hepatic cancer cells and the possible mechanism of action. Int J Mol Med. 42:1695–1715. 2018.PubMed/NCBI
36	You ML, Chen YJ, Chong QY, Wu MM, Pandey V, Chen RM, Liu L, Ma L, Wu ZS, Zhu T and Lobie PE: Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent. Oncotarget. 8:39323–39344. 2017. View Article : Google Scholar : PubMed/NCBI
37	Zhang Y, Li H, Chang H, Du L, Hai J, Geng X and Yan X: MTP18 overexpression contributes to tumor growth and metastasis and associates with poor survival in hepatocellular carcinoma. Cell Death Dis. 9:9562018. View Article : Google Scholar : PubMed/NCBI
38	Guamán-Ortiz LM, Orellana MI and Ratovitski EA: Natural compounds as modulators of non-apoptotic cell death in cancer cells. Curr Genomics. 18:132–155. 2017. View Article : Google Scholar : PubMed/NCBI
39	Aden DP, Fogel A, Plotkin S, Damjanov I and Knowles BB: Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature. 282:615–616. 1979. View Article : Google Scholar : PubMed/NCBI
40	Morris KM, Aden DP, Knowles BB and Colten HR: Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest. 70:906–913. 1982. View Article : Google Scholar : PubMed/NCBI
41	Nakabayashi H, Taketa K, Miyano K, Yamane T and Sato J: Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 42:3858–3863. 1982.PubMed/NCBI
42	Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, Siegelin MD, Fimognari C, Kumar NB, Dou QP, et al: Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol. 35 Suppl:S78–S103. 2015. View Article : Google Scholar : PubMed/NCBI
43	Panganiban RA, Snow AL and Day RM: Mechanisms of radiation toxicity in transformed and non-transformed cells. Int J Mol Sci. 14:15931–15958. 2013. View Article : Google Scholar : PubMed/NCBI
44	Kodama T, Hikita H, Kawaguchi T, Saito Y, Tanaka S, Shigekawa M, Shimizu S, Li W, Miyagi T, Kanto T, et al: The Bcl-2 homology domain 3 (BH3)-only proteins Bim and bid are functionally active and restrained by anti-apoptotic Bcl-2 family proteins in healthy liver. J Biol Chem. 288:30009–30018. 2013. View Article : Google Scholar : PubMed/NCBI
45	Bubici C and Papa S: JNK signalling in cancer: In need of new, smarter therapeutic targets. Br J Pharmacol. 171:24–37. 2014. View Article : Google Scholar : PubMed/NCBI
46	Calvo N, Carriere P, Martin MJ and Gentili C: RSK activation via ERK modulates human colon cancer cells response to PTHrP. J Mol Endocrinol. 59:13–27. 2017. View Article : Google Scholar : PubMed/NCBI
47	Kosako H and Kou M: Global Identification of ERK substrates by phosphoproteomics based on IMAC and 2D-DIGE. Methods Mol Biol 1487. 137–149. 2017. View Article : Google Scholar
48	Yao X, Liu H, Zhang X, Zhang L, Li X, Wang C and Sun S: Cell surface GRP78 accelerated breast cancer cell proliferation and migration by activating STAT3. PLoS One. 10:e01256342015. View Article : Google Scholar : PubMed/NCBI
49	Ishaq M, Kumar S, Varinli H, Han ZJ, Rider AE, Evans MD, Murphy AB and Ostrikov K: Atmospheric gas plasma-induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis. Mol Bio Cell. 25:1523–1531. 2014. View Article : Google Scholar
50	Hempel N and Trebak M: Crosstalk between Calcium and reactive oxygen species signaling in cancer. Cell Calcium. 63:70–96. 2017. View Article : Google Scholar : PubMed/NCBI
51	Hseu YC, Tsai TJ, Korivi M, Liu JY, Chen HJ, Lin CM, Shen YC and Yang HL: Antitumor properties of Coenzyme Q₀ against human ovarian carcinoma cells via induction of ROS-mediated apoptosis and cytoprotective autophagy. Sci Rep. 7:80622017. View Article : Google Scholar : PubMed/NCBI
52	Kim MO, Moon DO, Jung JM, Lee WS, Choi YH and Kim GY: Agaricus blazei extract induces apoptosis through ROS-dependent JNK activation involving the mitochondrial pathway and suppression of constitutive NF-κB in THP-1 cells. Evid Based Complement Alternat Med 2011. 8381722011.
53	Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, et al: NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J. 22:3898–3909. 2003. View Article : Google Scholar : PubMed/NCBI