Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Proapoptotic Effects of triazol-1,4-Naphthoquinones Involve Intracellular ROS Production and MAPK/ERK Pathway in Human Leukemia Cells

Author(s): Tangbadioa H. Coulidiati, Bruna B. Dantas, Glaucia V. Faheina-Martins, Enéas Ricardo de Morais Gomes, Juan C.R. Gonçalves* and Demetrius A. Machado de Araújo

Volume 20, Issue 17, 2020

Page: [2089 - 2098] Pages: 10

DOI: 10.2174/1871520620666200721124221

Price: $65

conference banner
Abstract

Background: The natural products constitute an important source of antitumor and cytotoxic agents. Naphthoquinones are effectively quinones present in different plants, with demonstrated anticancer activities. A recent study conducted by our group demonstrated the antileukemic potential of two novel triazol-1,4- naphthoquinones derivatives, PTN (2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1,4-naphthoquinone) and MPTN (2-[4- (4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1,4-naphthoquinone). Although, the mechanisms underlying the proapoptotic effects of PTN and MPTN have not been fully elucidated so far.

Objective: The aim of this study was to evaluate the proapoptotic mechanism of PTN and MPTN in human acute leukemia cells.

Methods: We used fluorescence microscopy to observe acridine orange and annexin V staining cells. Flow cytometry assay has also been used for ROS quantification, BAX and cytochrome c proteins expression and apoptosis analysis. MTT assay and western blotting technique have been performed as well for MAPK pathway analysis.

Results: By using the acridine orange and annexin V staining with fluorescence microscopy, we have characterized the proapoptotic effects of PTN and MPTN in HL-60 cells involving the intrinsic mitochondrial pathway, since these compounds promoted an increase in the intracellular BAX and cytochrome c protein levels (p<0.05). We further demonstrated that apoptosis induction in HL-60 cells was mediated by increasing intracellular ROS levels via ERK but not p38 MAPKs pathway.

Conclusion: Taken together, these results have demonstrated that PTN and MPTN are promising tools for the development of new anti-leukemic drugs.

Keywords: Cancer, acute leukemia, naphthoquinone, cytotoxicity, HL-60, reactive oxygen species.

« Previous Next »
Graphical Abstract

[1]
De Kouchkovsky, I.; Abdul-Hay, M. Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer J., 2016, 6(7)e441
[http://dx.doi.org/10.1038/bcj.2016.50] [PMID: 27367478]
[2]
Lai, C.; Doucette, K.; Norsworthy, K. Recent drug approvals for acute myeloid leukemia. J. Hematol. Oncol., 2019, 12(1), 100.
[http://dx.doi.org/10.1186/s13045-019-0774-x] [PMID: 31533852]
[3]
Shah, A.; Andersson, T.M-L.; Rachet, B.; Björkholm, M.; Lambert, P.C. Survival and cure of acute myeloid leukaemia in England, 1971-2006: A population-based study. Br. J. Haematol., 2013, 162(4), 509-516.
[http://dx.doi.org/10.1111/bjh.12425] [PMID: 23786647]
[4]
Meyers, J.; Yu, Y.; Kaye, J.A.; Davis, K.L. Medicare fee-for-service enrollees with primary acute myeloid leukemia: An analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl. Health Econ. Health Policy, 2013, 11(3), 275-286.
[http://dx.doi.org/10.1007/s40258-013-0032-2] [PMID: 23677706]
[5]
Kashyap, D.; Tuli, H.S.; Sak, K.; Garg, V.K.; Goel, N.; Punia, S.; Chaudhary, A. Role of reactive oxygen species in cancer progression. Curr. Pharmacol. Rep., 2019, 5, 79-86.
[http://dx.doi.org/10.1007/s40495-019-00171-y]
[6]
Yang, H.; Villani, R.M.; Wang, H.; Simpson, M.J.; Roberts, M.S.; Tang, M.; Liang, X. The role of cellular reactive oxygen species in cancer chemotherapy. J. Exp. Clin. Cancer Res., 2018, 37(1), 266.
[http://dx.doi.org/10.1186/s13046-018-0909-x] [PMID: 30382874]
[7]
Xian, D.; Lai, R.; Song, J.; Xiong, X.; Zhong, J. Emerging perspective: Role of increased ROS and redox imbalance in skin carcinogenesis. Oxid. Med. Cell. Longev., 2019, 20198127362
[http://dx.doi.org/10.1155/2019/8127362] [PMID: 31636809]
[8]
D’Sousa Costa, C.O.; Araujo Neto, J.H.; Baliza, I.R.S.; Dias, R.B.; Valverde, L.F.; Vidal, M.T.A.; Sales, C.B.S.; Rocha, C.A.G.; Moreira, D.R.M.; Soares, M.B.P.; Batista, A.A.; Bezerra, D.P. Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells. Oncotarget, 2017, 8(61), 104367-104392.
[http://dx.doi.org/10.18632/oncotarget.22248] [PMID: 29262647]
[9]
Bauer, D.; Werth, F.; Nguyen, H.A.; Kiecker, F.; Eberle, J. Critical role of Reactive Oxygen Species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells. Cell Death Dis., 2017, 8(2)e2594
[http://dx.doi.org/10.1038/cddis.2017.6] [PMID: 28151482]
[10]
Jeong, C-H.; Joo, S.H. Downregulation of reactive oxygen species in apoptosis. J. Cancer Prev., 2016, 21(1), 13-20.
[http://dx.doi.org/10.15430/JCP.2016.21.1.13] [PMID: 27051644]
[11]
Snezhkina, A.V.; Kudryavtseva, A.V.; Kardymon, O.L.; Savvateeva, M.V.; Melnikova, N.V.; Krasnov, G.S.; Dmitriev, A.A. ROS generation and antioxidant defense systems in normal and malignant cells. Oxid. Med. Cell. Longev., 2019, 20196175804
[http://dx.doi.org/10.1155/2019/6175804] [PMID: 31467634]
[12]
Li, H-Y.; Zhang, J.; Sun, L-L.; Li, B-H.; Gao, H-L.; Xie, T.; Zhang, N.; Ye, Z-M. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: An in vitro and in vivo study. Cell Death Dis., 2015, 6e1604
[http://dx.doi.org/10.1038/cddis.2014.543] [PMID: 25611379]
[13]
Seo, W.Y.; Goh, A.R.; Ju, S.M.; Song, H.Y.; Kwon, D-J.; Jun, J-G.; Kim, B.C.; Choi, S.Y.; Park, J. Celastrol induces expression of heme oxygenase-1 through ROS/Nrf2/ARE signaling in the HaCaT cells. Biochem. Biophys. Res. Commun., 2011, 407(3), 535-540.
[http://dx.doi.org/10.1016/j.bbrc.2011.03.053] [PMID: 21414301]
[14]
Xie, J-H.; Lai, Z-Q.; Zheng, X-H.; Xian, Y-F.; Li, Q.; Ip, S-P.; Xie, Y-L.; Chen, J-N.; Su, Z-R.; Lin, Z-X.; Yang, X-B. Apoptosis induced by bruceine D in human nonsmallcell lung cancer cells involves mitochondrial ROSmediated death signaling. Int. J. Mol. Med., 2019, 44(6), 2015-2026.
[http://dx.doi.org/10.3892/ijmm.2019.4363] [PMID: 31638181]
[15]
Massaoka, M.H.; Matsuo, A.L.; Figueiredo, C.R.; Farias, C.F.; Girola, N.; Arruda, D.C.; Scutti, J.A.B.; Romoff, P.; Favero, O.A.; Ferreira, M.J.P.; Lago, J.H.G.; Travassos, L.R. Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo. PLoS One, 2012, 7(6)e38698
[http://dx.doi.org/10.1371/journal.pone.0038698] [PMID: 22701695]
[16]
Bolton, J.L.; Dunlap, T. Formation and biological targets of quinones: Cytotoxic versus cytoprotective effects. Chem. Res. Toxicol., 2017, 30(1), 13-37.
[http://dx.doi.org/10.1021/acs.chemrestox.6b00256] [PMID: 27617882]
[17]
da Cruz, E.H.; Hussene, C.M.B.; Dias, G.G.; Diogo, E.B.T.; de Melo, I.M.; Rodrigues, B.L.; da Silva, M.G.; Valença, W.O.; Camara, C.A.; de Oliveira, R.N.; de Paiva, Y.G.; Goulart, M.O.F.; Cavalcanti, B.C.; Pessoa, C.; da Silva Júnior, E.N. 1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones. Bioorg. Med. Chem., 2014, 22(5), 1608-1619.
[http://dx.doi.org/10.1016/j.bmc.2014.01.033] [PMID: 24530030]
[18]
Wellington, K.W. Understanding cancer and the anticancer activities of naphthoquinones – a review. RSC Advances, 2015, 5, 20309-20338.
[http://dx.doi.org/10.1039/C4RA13547D]
[19]
Gonçalves, J.C.R.; Coulidiati, T.H.; Monteiro, A.L.; Carvalho-Gonçalves, L.C.T.; Valença, W.O.; Oliveira, R.N.; Câmara, C.A.; Araújo, D.A.M. Antitumoral activity of novel 1,4-naphthoquinone derivative involves L-type calcium channel activation in human colorectal cancer cell line. J. Appl. Biomed., 2016, 14(3), 229-234.
[http://dx.doi.org/10.1016/j.jab.2016.03.002]
[20]
Nascimento, W.S.; Camara, C.A.; Oliveira, R.N. Synthesis of 2-(1H-1,2,3-Triazol-1-Yl)-1,4-naphthoquinones from 2-azido-1,4-naphthoquinone and terminal alkynes. Synthesis, 2011, 2011(20), 3220-3224.
[http://dx.doi.org/10.1055/s-0030-1260172]
[21]
Coulidiati, T.H.; Dantas, B.B.; Faheina-Martins, G.V.; Gonçalves, J.C.R.; do Nascimento, W.S.; de Oliveira, R.N.; Camara, C.A.; Oliveira, E.J.; Lara, A.; Gomes, E.R.; Araújo, D.A.M. Distinct effects of novel naphtoquinone-based triazoles in human leukaemic cell lines. J. Pharm. Pharmacol., 2015, 67(12), 1682-1695.
[http://dx.doi.org/10.1111/jphp.12474] [PMID: 26256440]
[22]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[23]
Ravindran, J.; Gupta, N.; Agrawal, M.; Bala Bhaskar, A.S.; Lakshmana Rao, P.V. Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. Apoptosis, 2011, 16(2), 145-161.
[http://dx.doi.org/10.1007/s10495-010-0554-0] [PMID: 21082355]
[24]
Ghobrial, I.M.; Witzig, T.E.; Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin., 2005, 55(3), 178-194.
[http://dx.doi.org/10.3322/canjclin.55.3.178] [PMID: 15890640]
[25]
Gerl, R.; Vaux, D.L. Apoptosis in the development and treatment of cancer. Carcinogenesis, 2005, 26(2), 263-270.
[http://dx.doi.org/10.1093/carcin/bgh283] [PMID: 15375012]
[26]
Tan, B.L.; Norhaizan, M.E. Manilkara zapota (L.) P. Royen leaf water extract triggered apoptosis and activated caspase-dependent pathway in HT-29 human colorectal cancer cell line. Biomed. Pharmacother., 2019, 110, 748-757.
[http://dx.doi.org/10.1016/j.biopha.2018.12.027] [PMID: 30554113]
[27]
Indran, I.R.; Tufo, G.; Pervaiz, S.; Brenner, C. Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim. Biophys. Acta, 2011, 1807(6), 735-745.
[http://dx.doi.org/10.1016/j.bbabio.2011.03.010] [PMID: 21453675]
[28]
Firoozinia, M.; Moghadamtousi, S.Z.; Sadeghilar, A.; Karimian, H.; Noordin, M.I.B. Golden natural plant compounds activate apoptosis via both mitochondrial and death receptor pathways: A review. Electron. J. Biol., 2015, 11(3), 126-137.
[29]
Wang, K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis., 2014, 5(1)e996
[http://dx.doi.org/10.1038/cddis.2013.499]] [PMID: 24434519]
[30]
Jing, L.; He, M-T.; Chang, Y.; Mehta, S.L.; He, Q-P.; Zhang, J-Z.; Li, P.A. Coenzyme Q10 protects astrocytes from ROS-induced damage through inhibition of mitochondria-mediated cell death pathway. Int. J. Biol. Sci., 2015, 11(1), 59-66.
[http://dx.doi.org/10.7150/ijbs.10174] [PMID: 25552930]
[31]
Li, G-X.; Hu, H.; Jiang, C.; Schuster, T.; Lü, J. Differential involvement of reactive oxygen species in apoptosis induced by two classes of selenium compounds in human prostate cancer cells. Int. J. Cancer, 2007, 120(9), 2034-2043.
[http://dx.doi.org/10.1002/ijc.22480] [PMID: 17230520]
[32]
Hseu, Y.C.; Chang, W.H.; Chen, C.S.; Liao, J.W.; Huang, C.J.; Lu, F.J.; Chia, Y.C.; Hsu, H.K.; Wu, J.J.; Yang, H.L. Antioxidant activities of Toona sinensis leaves extracts using different antioxidant models. Food Chem. Toxicol., 2008, 46(1), 105-114.
[http://dx.doi.org/10.1016/j.fct.2007.07.003] [PMID: 17703862]
[33]
Palanivel, K.; Kanimozhi, V.; Kadalmani, B.; Akbarsha, M.A.; Verrucarin, A. Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells. J. Cell. Biochem., 2014, 115(11), 2022-2032.
[http://dx.doi.org/10.1002/jcb.24874] [PMID: 24963595]
[34]
Zhang, Y.; Zheng, S.; Zheng, J-S.; Wong, K-H.; Huang, Z.; Ngai, S-M.; Zheng, W.; Wong, Y-S.; Chen, T. Synergistic induction of apoptosis by methylseleninic acid and cisplatin, the role of ROS-ERK/AKT-p53 pathway. Mol. Pharm., 2014, 11(4), 1282-1293.
[http://dx.doi.org/10.1021/mp400749f] [PMID: 24555485]
[35]
Park, S.H.; Sung, J.H.; Kim, E.J.; Chung, N.; Park, S.H.; Sung, J.H.; Kim, E.J.; Chung, N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz. J. Med. Biol. Res., 2015, 48(2), 111-119.
[http://dx.doi.org/10.1590/1414-431x20144293] [PMID: 25517919]
[36]
Xu, H.; Li, X.; Ding, W.; Zeng, X.; Kong, H.; Wang, H.; Xie, W. Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway. Cancer Cell Int., 2015, 15, 25.
[http://dx.doi.org/10.1186/s12935-015-0166-4] [PMID: 25741219]
[37]
Kuo, P-L.; Chen, C-Y.; Hsu, Y-L. Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. Cancer Res., 2007, 67(15), 7406-7420.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1089] [PMID: 17671211]
[38]
Sun, X.; Ai, M.; Wang, Y.; Shen, S.; Gu, Y.; Jin, Y.; Zhou, Z.; Long, Y.; Yu, Q. Selective induction of tumor cell apoptosis by a novel P450-mediated Reactive Oxygen Species (ROS) inducer methyl 3-(4-nitrophenyl) propiolate. J. Biol. Chem., 2013, 288(13), 8826-8837.
[http://dx.doi.org/10.1074/jbc.M112.429316] [PMID: 23382387]
[39]
Hileman, E.O.; Liu, J.; Albitar, M.; Keating, M.J.; Huang, P. Intrinsic oxidative stress in cancer cells: A biochemical basis for therapeutic selectivity. Cancer Chemother. Pharmacol., 2004, 53(3), 209-219.
[http://dx.doi.org/10.1007/s00280-003-0726-5] [PMID: 14610616]
[40]
McCubrey, J.A.; Steelman, L.S.; Chappell, W.H.; Abrams, S.L.; Wong, E.W.T.; Chang, F.; Lehmann, B.; Terrian, D.M.; Milella, M.; Tafuri, A.; Stivala, F.; Libra, M.; Basecke, J.; Evangelisti, C.; Martelli, A.M.; Franklin, R.A. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta, 2007, 1773(8), 1263-1284.
[http://dx.doi.org/10.1016/j.bbamcr.2006.10.001] [PMID: 17126425]
[41]
Niu, C-C.; Zhao, C.; Yang, Z.; Zhang, X-L.; Pan, J.; Zhao, C.; Si, W-K. Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway. Cancer Cell Int., 2014, 14, 74.
[http://dx.doi.org/10.1186/s12935-014-0074-z] [PMID: 25187756]
[42]
Wu, Z-J.; Yu, J.; Fang, Q-J.; Wang, R-X.; Lian, J-B.; He, R-L.; Jiao, H-X.; Lin, M-J. Sodium ferulate prevents daunorubicin--induced apoptosis in H9c2 cells via inhibition of the ERKs pathway. Cell. Physiol. Biochem., 2015, 36(6), 2121-2136.
[http://dx.doi.org/10.1159/000430179] [PMID: 26279420]

Rights & Permissions Print Cite
Article Metrics
32
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy