Investigation of the effects of catharanthine and Q10 on Nrf2 and its association with MMP-9, MRP1, and Bcl-2 and apoptosis in a model of hepatocellular carcinoma.
Humans
Antioxidants
/ pharmacology
Carcinoma, Hepatocellular
/ drug therapy
NF-E2-Related Factor 2
/ metabolism
Kelch-Like ECH-Associated Protein 1
/ metabolism
Matrix Metalloproteinase 9
/ metabolism
Liver Neoplasms
/ drug therapy
Oxidative Stress
Hep G2 Cells
Apoptosis
Vinca Alkaloids
Multidrug Resistance-Associated Proteins
Apoptosis
Catharanthine
Drug resistance
HepG2 cell
Metastasis
Q10
Ubiquinone
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
04 2024
04 2024
Historique:
received:
27
08
2023
accepted:
02
10
2023
medline:
14
3
2024
pubmed:
19
10
2023
entrez:
19
10
2023
Statut:
ppublish
Résumé
Since the role of Nrf2 in cancer cell survival has been highlighted, the pharmacological modulation of the Nrf2-Keap1 pathway may provide new opportunities for cancer treatment. This study purposed to use ubiquinone (Q10) as an antioxidant and catharanthine alkaloid as a cAMP inducer suppressing HepG2 cells by reducing Nrf2 level. The effects of Q10 and catharanthine on HepG2 cells in terms of viability were analyzed by MTT test. MTT results were used to determine the effective concentration of both drugs for the subsequent treatment and analysis. Subsequently, the effects of Q10 and catharanthine in a single and combined manner on oxidant/antioxidant status, apoptosis, metastasis, and drug resistance of HepG2 cells were investigated by related methods. Both Q10 and catharanthine decreased the level of oxidative stress products and increased antioxidant capacity in HepG2 cells. Nrf2 gene expression decreased by Q10, but catharanthine unexpectedly increased it. Following Nrf2 alterations, the expression levels of MMP-9 and MRP1 involved in metastasis and drug resistance were significantly and dose-dependently decreased by Q10, while catharanthine slightly increased both. However, both drugs increased caspase 3/7 activity and apoptosis rate, and the effect of Q10 on apoptosis was stronger than that of catharanthine. Most of the effects of the combination treatments were similar to those of the Q10 single treatment and indicated the dominant effect over the catharanthine component. Despite the antioxidant and apoptotic properties of both agents, Q10 was better than catharanthine in inducing apoptosis, counteracting drug resistance, and metastasis in HepG2 cells.
Identifiants
pubmed: 37855932
doi: 10.1007/s00210-023-02767-0
pii: 10.1007/s00210-023-02767-0
doi:
Substances chimiques
Antioxidants
0
multidrug resistance-associated protein 1
Y49M64GZ4Q
NF-E2-Related Factor 2
0
catharanthine
WT0YJV846J
Kelch-Like ECH-Associated Protein 1
0
Matrix Metalloproteinase 9
EC 3.4.24.35
Vinca Alkaloids
0
Multidrug Resistance-Associated Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2507-2522Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Akbari A, Mobini GR, Agah S, Morvaridzadeh M, Omidi A, Potter E, Fazelian S, Ardehali SH, Daneshzad E, Dehghani S (2020) Coenzyme Q10 supplementation and oxidative stress parameters: a systematic review and meta-analysis of clinical trials. Eur J Clin Pharmacol 76:1483–1499
pubmed: 32583356
Aslam M, Ladilov Y (2022) Emerging role of cAMP/AMPK signaling. Cells 11:308
pubmed: 35053423
pmcid: 8774420
Chen R, Cui J, Xu C, Xue T, Guo K, Gao D, Liu Y, Ye S, Ren Z (2012) The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann Surg Oncol 19(Suppl 3):S375-384
pubmed: 21681378
Chen S, Zhang Z, Wu Y, Shi Q, Yan H, Mei N, Tolleson WH, Guo L (2015) Endoplasmic reticulum stress and store-operated calcium entry contribute to usnic acid-induced toxicity in hepatic cells. Toxicol Sci 146:116–126
pubmed: 25870318
Cheng Y, Zhang J, Guo W, Li F, Sun W, Chen J, Zhang C, Lu X, Tan Y, Feng W, Fu Y, Liu GC, Xu Z, Cai L (2016) Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radical Biol Med 93:94–109
Ehrhardt H, Schrembs D, Moritz C, Wachter F, Haldar S, Graubner U, Nathrath M, Jeremias I (2011) Optimized anti-tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule. Blood 118:6123–6131
pubmed: 21926351
Elsby R, Kitteringham NR, Goldring CE, Lovatt CA, Chamberlain M, Henderson CJ, Wolf CR, Park BK (2003) Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi. J Biol Chem 278:22243–22249
pubmed: 12646564
Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F (2006) p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281:39776–39784
pubmed: 17077087
Filipeanu CM, Nelemans A, Veldman RJ, de Zeeuw D, Kok JW (2000) Regulation of [Ca(2+)](i) homeostasis in MRP1 overexpressing cells. FEBS Lett 474:107–110
pubmed: 10828460
Fox DB, Garcia NMG, McKinney BJ, Lupo R, Noteware LC, Newcomb R, Liu J, Locasale JW, Hirschey MD, Alvarez JV (2020) NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism. Nat Metab 2:318–334
pubmed: 32691018
pmcid: 7370851
Fu Y, Chung FL (2018) Oxidative stress and hepatocarcinogenesis. Hepatoma Res 4:39
pubmed: 30761356
pmcid: 6370311
Garrido Ruiz D, Sandoval-Perez A, Rangarajan AV, Gunderson EL, Jacobson MP (2022) Cysteine oxidation in proteins: structure, biophysics, and simulation. Biochemistry 61:2165–2176
pubmed: 36161872
Gong P, Cederbaum AI (2006) Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology (Baltimore, MD) 43:144–153
pubmed: 16374848
Grek CL, Zhang J, Manevich Y, Townsend DM, Tew KD (2013) Causes and consequences of cysteine S-glutathionylation. J Biol Chem 288:26497–26504
pubmed: 23861399
pmcid: 3772197
Haque E, Karim MR, Salam Teeli A, Śmiech M, Leszczynski P, Winiarczyk D, Parvanov ED, Atanasov AG, Taniguchi H (2020) Molecular mechanisms underlying hepatocellular carcinoma induction by aberrant NRF2 activation-mediated transcription networks: interaction of NRF2-KEAP1 controls the fate of hepatocarcinogenesis. Int J Mol Sci 21:5378
pubmed: 32751080
pmcid: 7432811
Hayes JD, Dinkova-Kostova AT, Tew KD (2020) Oxidative stress in cancer. Cancer Cell 38:167–197
pubmed: 32649885
pmcid: 7439808
Heidari-Kalvani N, Fallah S, Barjasteh F, Bahreini E (2023) Effects of ubiquinone on oxidant and antioxidant status in hepatocellular carcinoma cell line. Int J Med Lab 10(1):75–82
Huo J, Xu Z, Hosoe K, Kubo H, Miyahara H, Dai J, Mori M, Sawashita J, Higuchi K (2018) Coenzyme Q10 prevents senescence and dysfunction caused by oxidative stress in vascular endothelial cells. Oxid Med Cell Longev 2018:3181759
pubmed: 30116476
pmcid: 6079399
Jaworska M, Szczudło J, Pietrzyk A, Shah J, Trojan SE, Ostrowska B, Kocemba-Pilarczyk KA (2023) The Warburg effect: a score for many instruments in the concert of cancer and cancer niche cells. Pharmacol Rep 75:876–890
pubmed: 37332080
pmcid: 10374743
Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868
pubmed: 11683914
Khodakarami A, Adibfar S, Karpisheh V, Abolhasani S, Jalali P, Mohammadi H, Gholizadeh Navashenaq J, Hojjat-Farsangi M, Jadidi-Niaragh F (2022) The molecular biology and therapeutic potential of Nrf2 in leukemia. Cancer Cell Int 22:241
pubmed: 35906617
pmcid: 9336077
Kim H, Xue X (2020) Detection of total reactive oxygen species in adherent cells by 2’,7’-dichlorodihydrofluorescein diacetate staining. J Vis Exp. https://doi.org/10.3791/60682
doi: 10.3791/60682
pubmed: 33346204
Kotani M, Koizumi Y, Yamada T, Kawasaki A, Akabane T (1978) Increase of cyclic adenosine 3’:5’-monophosphate concentration in transplantable lymphoma cells by vinca alkaloids. Cancer Res 38:3094–3099
pubmed: 209896
Kryszczuk M, Kowalczuk O (2022) Significance of NRF2 in physiological and pathological conditions an comprehensive review. Arch Biochem Biophys 730:109417
pubmed: 36202215
Kumari S, Badana AK, G MM, G S, Malla R (2018) Reactive oxygen species: a key constituent in cancer survival. Biomark Insights 13:1177271918755391
pubmed: 29449774
pmcid: 5808965
Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892
pubmed: 11940647
pmcid: 133753
Li G, Chen X, Wang Q, Xu Z, Zhang W, Ye L (2007) The roles of four multi-drug resistance proteins in hepatocellular carcinoma multidrug resistance. J Huazhong Univ Sci Technolog Med Sci 27(2):173–175
Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218
pubmed: 26778478
pmcid: 4783224
Macáková K, Afonso R, Saso L, Mladěnka P (2019) The influence of alkaloids on oxidative stress and related signaling pathways. Free Radic Biol Med 134:429–444
pubmed: 30703480
Maher JM, Cheng X, Slitt AL, Dieter MZ, Klaassen CD (2005) Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver. Drug Metab Dispos 33:956–962
pubmed: 15833929
Marinho HS, Real C, Cyrne L, Soares H, Antunes F (2014) Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox Biol 2:535–562
pubmed: 24634836
pmcid: 3953959
Marsh SA, Laursen PB, Coombes JS (2006) Effects of antioxidant supplementation and exercise training on erythrocyte antioxidant enzymes. Int J Vitam Nutr Res 76:324–331
pubmed: 17245671
Massimi M, Ragusa F, Cardarelli S, Giorgi M (2019) Targeting cyclic AMP signalling in hepatocellular carcinoma. Cells 8(12):1511
Mika D, Richter W, Conti M (2015) A CaMKII/PDE4D negative feedback regulates cAMP signaling. Proc Natl Acad Sci U S A 112:2023–2028
pubmed: 25646485
pmcid: 4343159
Milkovic L, Zarkovic N, Saso L (2017) Controversy about pharmacological modulation of Nrf2 for cancer therapy. Redox Biol 12:727–732
pubmed: 28411557
pmcid: 5393166
Mohamed HA, Said RS (2021) Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB/TGF-β/MMP-9 pathways. Int Immunopharmacol 92:107347
pubmed: 33418245
Nakamura H, Takada K (2021) Reactive oxygen species in cancer: current findings and future directions. Cancer Sci 112:3945–3952
pubmed: 34286881
pmcid: 8486193
Nart D, Yaman B, Yilmaz F, Zeytunlu M, Karasu Z, Kiliç M (2010) Expression of matrix metalloproteinase-9 in predicting prognosis of hepatocellular carcinoma after liver transplantation. Liver Transpl 16:621–630
pubmed: 20440771
Niture SK, Jaiswal AK (2012) Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem 287:9873–9886
pubmed: 22275372
pmcid: 3323009
Oztopcu-Vatan P, Sayitoglu M, Gunindi M, Inan E (2015) Cytotoxic and apoptotic effects of menadione on rat hepatocellular carcinoma cells. Cytotechnology 67:1003–1009
pubmed: 24828824
Parker T, Wang KW, Manning D, Dart C (2019) Soluble adenylyl cyclase links Ca(2+) entry to Ca(2+)/cAMP-response element binding protein (CREB) activation in vascular smooth muscle. Sci Rep 9:7317
pubmed: 31086231
pmcid: 6514005
Raghunath A, Sundarraj K, Arfuso F, Sethi G, Perumal E (2018) Dysregulation of Nrf2 in hepatocellular carcinoma: role in cancer progression and chemoresistance. Cancers (Basel) 10(12):481
Rieger AM, Nelson KL, Konowalchuk JD, Barreda DR (2011) Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J Vis Exp. https://doi.org/10.3791/2597
doi: 10.3791/2597
pubmed: 21540825
pmcid: 3169266
Rubio CP, Hernández-Ruiz J, Martinez-Subiela S, Tvarijonaviciute A, Ceron JJ (2016) Spectrophotometric assays for total antioxidant capacity (TAC) in dog serum: an update. BMC Vet Res 12:166
pubmed: 27526688
pmcid: 4986369
Sakamoto K, Iwasaki K, Sugiyama H, Tsuji Y (2009) Role of the tumor suppressor PTEN in antioxidant responsive element-mediated transcription and associated histone modifications. Mol Biol Cell 20:1606–1617
pubmed: 19158375
pmcid: 2655256
Salih AM, Smith DM, Price JF, Dawson LE (1987) Modified extraction 2-thiobarbituric acid method for measuring lipid oxidation in poultry1. Poult Sci 66:1483–1488
pubmed: 3684874
Samimi F, Baazm M, Eftekhar E, Rajabi S, Goodarzi MT, Jalali Mashayekhi F (2019) Possible antioxidant mechanism of coenzyme Q10 in diabetes: impact on Sirt1/Nrf2 signaling pathways. Res Pharm Sci 14:524–533
pubmed: 32038732
pmcid: 6937743
Sha L, Lv Z, Liu Y, Zhang Y, Sui X, Wang T, Zhang H (2021) Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer. Mol Med Rep 24(2):560
Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Munuera-Cabeza M, Suárez-Carrillo A, Talaverón-Rey M, Sánchez-Alcázar JA (2021) Coenzyme Q
Sun Z, Chin YE, Zhang DD (2009a) Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol 29:2658–2672
pubmed: 19273602
pmcid: 2682049
Sun Z, Huang Z, Zhang DD (2009b) Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS ONE 4:e6588
pubmed: 19668370
pmcid: 2719090
Suresh D, Srinivas AN, Kumar DP (2020) Etiology of hepatocellular carcinoma: special focus on fatty liver disease. Front Oncol 10:601710
pubmed: 33330100
pmcid: 7734960
Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123–140
pubmed: 21251164
Tari C, Fournier N, Briand C, Ducet G, Crevat A (1986) Action of vinca alkaloides on calcium movements through mitochondrial membrane. Pharmacol Res Commun 18:519–528
pubmed: 3749242
Tarry-Adkins JL, Fernandez-Twinn DS, Hargreaves IP, Neergheen V, Aiken CE, Martin-Gronert MS, McConnell JM, Ozanne SE (2016) Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth. Am J Clin Nutr 103:579–588
pubmed: 26718412
Tian S, Wang D, Li X, Tang J, Han G, Dai Y (2013) Coenzyme Q10 enhances the expression of Bcl-2 and inhibits the expressions of Bax and GSK-3β in the hippocampus of rats exposed to ischemia/reperfusion injury. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 29:698–701
pubmed: 23837978
van der Reest J, Lilla S, Zheng L, Zanivan S, Gottlieb E (2018) Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress. Nat Commun 9:1581
pubmed: 29679077
pmcid: 5910380
Watanabe K, Williams EF, Law JS, West WL (1981) Effects of vinca alkaloids on calcium-calmodulin regulated cyclic adenosine 3’,5’-monophosphatase phosphodiesterase activity from brain. Biochem Pharmacol 30:335–340
pubmed: 6260119
Wu Y, Zhang J, Li C, Hu H, Qin B, Wang T, Lu Y, Wang S (2021) The activation of ROS/NF-κB/MMP-9 pathway promotes calcium-induced kidney crystal deposition. Oxid Med Cell Longev 2021:8836355
pubmed: 34211634
pmcid: 8208877
Xu C, Li CY, Kong AN (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 28:249–268
pubmed: 15832810
Xu Z, Huo J, Ding X, Yang M, Li L, Dai J, Hosoe K, Kubo H, Mori M, Higuchi K, Sawashita J (2017) Coenzyme Q10 improves lipid metabolism and ameliorates obesity by regulating CaMKII-mediated PDE4 inhibition. Sci Rep 7:8253
pubmed: 28811612
pmcid: 5557856
Yan H, Zhang B, Li S, Zhao Q (2010) A formal model for analyzing drug combination effects and its application in TNF-α-induced NFκB pathway. BMC Syst Biol 4:50
pubmed: 20416113
pmcid: 2873319
Yi G, Din JU, Zhao F, Liu X (2020) Effect of soybean peptides against hydrogen peroxide induced oxidative stress in HepG2 cells via Nrf2 signaling. Food Funct 11:2725–2737
pubmed: 32167099
Zhang M, Zhang C, Zhang L, Yang Q, Zhou S, Wen Q, Wang J (2015) Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma. BMC Cancer 15:531
pubmed: 26194347
pmcid: 4507320
Zhang D, Jin W, Liu H, Liang T, Peng Y, Zhang J, Zhang Y (2020) ENT1 inhibition attenuates apoptosis by activation of cAMP/pCREB/Bcl2 pathway after MCAO in rats. Exp Neurol 331:113362
pubmed: 32445645
Zhang J, Zhang Q, Li H, Chen X, Liu W, Liu X (2021) Antioxidant activity of SSeCAHK in HepG2 cells: a selenopeptide identified from selenium-enriched soybean protein hydrolysates. RSC Adv 11:33872–33882
pubmed: 35497303
pmcid: 9042330
Zhao X, Benveniste EN (2008) Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators. J Mol Biol 383:945–956
pubmed: 18790699
pmcid: 2748421
Zhao J, Yu BY, Wang DY, Yang JE (2010) Promoter polymorphism of MRP1 associated with reduced survival in hepatocellular carcinoma. World J Gastroenterol 16:6104–6110
pubmed: 21182225
pmcid: 3012574
Zimta AA, Cenariu D, Irimie A, Magdo L, Nabavi SM, Atanasov AG, Berindan-Neagoe I (2019) The role of Nrf2 activity in cancer development and progression. Cancers (Basel) 11(11):1755