Generic placeholder image

Current Cancer Drug Targets

Author(s): Tatiana A. Fedotcheva and Nadezhda I. Fedotcheva*

DOI: 10.2174/1568009621999210120192558

DownloadDownload PDF Flyer Cite As
Protectors of the Mitochondrial Permeability Transition Pore Activated by Iron and Doxorubicin

Page: [514 - 525] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Aim: The study is aimed at examining of action of iron, DOX, and their complex on the Mitochondrial Permeability Transition Pore (MPTP) opening and detecting of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis.

Background: The Toxicity of Doxorubicin (DOX) is mainly associated with free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by membrane damage. The Mitochondrial Permeability Transition Pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca2+ -induced MPTP opening in the presence of iron has not yet been studied.

Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate- ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. The iron chelator deferoxamine (DFO), the lipid radical scavenger butyl-hydroxytoluene (BHT), and rutenium red (Rr), as a possible inhibitor of ferrous ions uptake in mitochondria, were tested as MPTP protectors. The role of medium alkalization was also examined.

Methods: Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca2+ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of Succinate Dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP.

Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca2+ -induced MPTP opening, acting in different stages of MPTP activation.

These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction.

Keywords: Doxorubicin, iron, mitochondrial permeability transition pore, butylhydroxytoluene, alkalization, deferoxamine.

Graphical Abstract

[1]
Ichikawa, Y.; Ghanefar, M.; Bayeva, M.; Wu, R.; Khechaduri, A.; Naga Prasad, S.V.; Mutharasan, R.K.; Naik, T.J.; Ardehali, H. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest., 2014, 124(2), 617-630.
[http://dx.doi.org/10.1172/JCI72931] [PMID: 24382354]
[2]
Kuznetsov, A.V.; Margreiter, R.; Amberger, A.; Saks, V.; Grimm, M. Changes in mitochondrial redox state, membrane potential and calcium precede mitochondrial dysfunction in doxorubicin-induced cell death. Biochim. Biophys. Acta, 2011, 1813(6), 1144-1152.
[http://dx.doi.org/10.1016/j.bbamcr.2011.03.002] [PMID: 21406203]
[3]
Pereira, G.C.; Pereira, S.P.; Pereira, C.V.; Lumini, J.A.; Magalhães, J.; Ascensão, A.; Santos, M.S.; Moreno, A.J.; Oliveira, P.J. Mitochondrionopathy phenotype in doxorubicin-treated Wistar rats depends on treatment protocol and is cardiac-specific. PLoS One, 2012, 7(6), e38867.
[http://dx.doi.org/10.1371/journal.pone.0038867] [PMID: 22745682]
[4]
Zhou, S.; Starkov, A.; Froberg, M.K.; Leino, R.L.; Wallace, K.B. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res., 2001, 61(2), 771-777.
[PMID: 11212281]
[5]
Carvalho, F.S.; Burgeiro, A.; Garcia, R.; Moreno, A.J.; Carvalho, R.A.; Oliveira, P.J. Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev., 2014, 34(1), 106-135.
[http://dx.doi.org/10.1002/med.21280] [PMID: 23494977]
[6]
Saad, S.Y.; Najjar, T.A.; Al-Rikabi, A.C. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol. Res., 2001, 43(3), 211-218.
[http://dx.doi.org/10.1006/phrs.2000.0769] [PMID: 11401411]
[7]
Santos-Alves, E.; Rizo-Roca, D.; Marques-Aleixo, I.; Coxito, P.; Martins, S.; Guimarães, J.T.; Oliveira, P.J.; Torrella, J.R.; Magalhães, J.; Ascensão, A. Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling. Mitochondrion, 2019, 47, 103-113.
[http://dx.doi.org/10.1016/j.mito.2019.05.008] [PMID: 31170523]
[8]
Fang, X.; Wang, H.; Han, D.; Xie, E.; Yang, X.; Wei, J.; Gu, S.; Gao, F.; Zhu, N.; Yin, X.; Cheng, Q.; Zhang, P.; Dai, W.; Chen, J.; Yang, F.; Yang, H.T.; Linkermann, A.; Gu, W.; Min, J.; Wang, F. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl. Acad. Sci. USA, 2019, 116(7), 2672-2680.
[http://dx.doi.org/10.1073/pnas.1821022116] [PMID: 30692261]
[9]
Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev., 2004, 56(2), 185-229.
[http://dx.doi.org/10.1124/pr.56.2.6] [PMID: 15169927]
[10]
Xu, X.; Persson, H.L.; Richardson, D.R. Molecular pharmacology of the interaction of anthracyclines with iron. Mol. Pharmacol., 2005, 68(2), 261-271.
[http://dx.doi.org/10.1124/mol.105.013383] [PMID: 15883202]
[11]
Gammella, E; Maccarinelli, F; Buratti, P; Recalcati, S; Cairo, G The role of iron in anthracycline cardiotoxicity. Front Pharmacol., 2014, 5, 25.
[http://dx.doi.org/10.3389/fphar.2014.00025]
[12]
Asensio-López, M.C.; Soler, F.; Sánchez-Más, J.; Pascual-Figal, D.; Fernández-Belda, F.; Lax, A. Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes. Arch. Biochem. Biophys., 2016, 594, 26-36.
[http://dx.doi.org/10.1016/j.abb.2016.02.021] [PMID: 26906075]
[13]
Cardoso, S.; Santos, R.X.; Carvalho, C.; Correia, S.; Pereira, G.C.; Pereira, S.S.; Oliveira, P.J.; Santos, M.S.; Proença, T.; Moreira, P.I. Doxorubicin increases the susceptibility of brain mitochondria to Ca(2+)-induced permeability transition and oxidative damage. Free Radic. Biol. Med., 2008, 45(10), 1395-1402.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.08.008] [PMID: 18775776]
[14]
Gogvadze, V.; Walter, P.B.; Ames, B.N. The role of Fe2+-induced lipid peroxidation in the initiation of the mitochondrial permeability transition. Arch. Biochem. Biophys., 2003, 414(2), 255-260.
[http://dx.doi.org/10.1016/S0003-9861(02)00750-6] [PMID: 12781777]
[15]
Finn, N.A.; Kemp, M.L. Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells. Mol. Biosyst., 2012, 8(2), 650-662.
[http://dx.doi.org/10.1039/C1MB05315A] [PMID: 22134636]
[16]
Oliveira, P.J.; Santos, M.S.; Wallace, K.B. Doxorubicin-induced thiol-dependent alteration of cardiac mitochondrial permeability transition and respiration. Biochemistry (Mosc.), 2006, 71(2), 194-199.
[http://dx.doi.org/10.1134/S000629790602012X] [PMID: 16489925]
[17]
Wongjaikam, S.; Kumfu, S.; Khamseekaew, J.; Chattipakorn, S.C.; Chattipakorn, N. Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine. Sci. Rep., 2017, 7, 44460.
[http://dx.doi.org/10.1038/srep44460] [PMID: 28287621]
[18]
Al-Shabanah, O.A.; Aleisa, A.M.; Hafez, M.M.; Al-Rejaie, S.S.; Al-Yahya, A.A.; Bakheet, S.A.; Al-Harbi, M.M.; Sayed-Ahmed, M.M. Desferrioxamine attenuates doxorubicin-induced acute cardiotoxicity through TFG-β/Smad p53 pathway in rat model. Oxid. Med. Cell. Longev., 2012, 2012, 619185.
[http://dx.doi.org/10.1155/2012/619185] [PMID: 22619697]
[19]
Xu, X.; Sutak, R.; Richardson, D.R. Iron chelation by clinically relevant anthracyclines: alteration in expression of iron-regulated genes and atypical changes in intracellular iron distribution and trafficking. Mol. Pharmacol., 2008, 73(3), 833-844.
[http://dx.doi.org/10.1124/mol.107.041335] [PMID: 18029550]
[20]
Hasinoff, B.B.; Schnabl, K.L.; Marusak, R.A.; Patel, D.; Huebner, E. Dexrazoxane (ICRF-187) protects cardiac myocytes against doxorubicin by preventing damage to mitochondria. Cardiovasc. Toxicol., 2003, 3(2), 89-99.
[http://dx.doi.org/10.1385/CT:3:2:89] [PMID: 14501028]
[21]
Shi, W.; Deng, H.; Zhang, J.; Zhang, Y.; Zhang, X.; Cui, G. Mitochondria-targeting small molecules effectively prevent cardiotoxicity induced by doxorubicin. Molecules, 2018, 23(6), 1486.
[http://dx.doi.org/10.3390/molecules23061486] [PMID: 29921817]
[22]
Tadokoro, T.; Ikeda, M.; Ide, T.; Deguchi, H.; Ikeda, S.; Okabe, K.; Ishikita, A.; Matsushima, S.; Koumura, T.; Yamada, K.I.; Imai, H.; Tsutsui, H. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight, 2020, 5(9), e132747.
[http://dx.doi.org/10.1172/jci.insight.132747] [PMID: 32376803]
[23]
Fedotcheva, N.I.; Mokhova, E.N. Mitochondrial models of pathologies with oxidative stress. Efficiency of alkalization to reduce mitochondrial damage. Biochemistry (Mosc.), 2013, 78(11), 1293-1297.
[http://dx.doi.org/10.1134/S0006297913110102] [PMID: 24460944]
[24]
Fedotcheva, T.A.; Teplova, V.V.; Fedotcheva, N.I. Activation of calcium-dependent cyclosporine-sensitive mitochondrial pores with doxorubicin in combination with iron ions. Биол. мембраны, 2018, 35(1), 79-84.
[http://dx.doi.org/10.7868/S0233475518010097]
[25]
Fedotcheva, N.I.; Teplova, V.V.; Fedotcheva, T.A.; Rzheznikov, V.M.; Shimanovskii, N.L. Effect of progesterone and its synthetic analogues on the activity of mitochondrial permeability transition pore in isolated rat liver mitochondria. Biochem. Pharmacol., 2009, 78(8), 1060-1068.
[http://dx.doi.org/10.1016/j.bcp.2009.05.028] [PMID: 19481064]
[26]
Dynnik, V.V.; Grishina, E.V.; Fedotcheva, N.I. The mitochondrial NO-synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore. FEBS J., 2020, 287(8), 1525-1536.
[http://dx.doi.org/10.1111/febs.15090] [PMID: 31602795]
[27]
Guo, L.; Shestov, A.A.; Worth, A.J.; Nath, K.; Nelson, D.S.; Leeper, D.B.; Glickson, J.D.; Blair, I.A. Inhibition of mitochondrial complex II by the anticancer agent lonidamine. J. Biol. Chem., 2016, 291(1), 42-57.
[http://dx.doi.org/10.1074/jbc.M115.697516] [PMID: 26521302]
[28]
Beloborodova, N.; Pautova, A.; Sergeev, A.; Fedotcheva, N. Serum levels of mitochondrial and microbial metabolites reflect mitochondrial dysfunction in different stages of sepsis. Metabolites, 2019, 9(10), 196.
[http://dx.doi.org/10.3390/metabo9100196] [PMID: 31547099]
[29]
Muraoka, S.; Miura, T. Inactivation of mitochondrial succinate dehydrogenase by adriamycin activated by horseradish peroxidase and hydrogen peroxide. Chem. Biol. Interact., 2003, 145(1), 67-75.
[http://dx.doi.org/10.1016/S0009-2797(02)00239-9] [PMID: 12606155]
[30]
Link, G.; Saada, A.; Pinson, A.; Konijn, A.M.; Hershko, C. Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. J. Lab. Clin. Med., 1998, 131(5), 466-474.
[http://dx.doi.org/10.1016/S0022-2143(98)90148-2] [PMID: 9605112]
[31]
Zhang, X.; Lemasters, J.J. Translocation of iron from lysosomes to mitochondria during ischemia predisposes to injury after reperfusion in rat hepatocytes. Free Radic. Biol. Med., 2013, 63, 243-253.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.05.004] [PMID: 23665427]
[32]
Zhang, L.; Wang, H.; Zhou, X.; Mao, L.; Ding, K.; Hu, Z. Role of mitochondrial calcium uniporter-mediated Ca2+ and iron accumulation in traumatic brain injury. J. Cell. Mol. Med., 2019, 23(4), 2995-3009.
[http://dx.doi.org/10.1111/jcmm.14206] [PMID: 30756474]
[33]
Sripetchwandee, J.; Sanit, J.; Chattipakorn, N.; Chattipakorn, S.C. Mitochondrial calcium uniporter blocker effectively prevents brain mitochondrial dysfunction caused by iron overload. Life Sci., 2013, 92(4-5), 298-304.
[http://dx.doi.org/10.1016/j.lfs.2013.01.004] [PMID: 23333832]
[34]
Huang, X.; Liu, Y.; Yang, X.; Lai, S.; Zhang, Y.; Gu, J.; Li, H.; Xie, Y.; Xia, Y. NH4Cl treatment prevents doxorubicin-induced myocardial dysfunction in vivo. Life Sci., 2019, 227, 94-100.
[http://dx.doi.org/10.1016/j.lfs.2019.04.044] [PMID: 31004659]
[35]
Ichas, F.; Mazat, J.P. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim. Biophys. Acta, 1998, 1366(1-2), 33-50.
[http://dx.doi.org/10.1016/S0005-2728(98)00119-4] [PMID: 9714722]
[36]
Elustondo, P.A.; Negoda, A.; Kane, C.L.; Kane, D.A.; Pavlov, E.V. Spermine selectively inhibits high-conductance, but not low- conductance calcium-induced permeability transition pore. Biochim. Biophys. Acta, 2015, 1847(2), 231-240.
[http://dx.doi.org/10.1016/j.bbabio.2014.10.007] [PMID: 25448536]
[37]
Kakkar, P.; Mehrotra, S.; Viswanathan, P.N. tBHP induced in vitro swelling of rat liver mitochondria. Mol. Cell. Biochem., 1996, 154(1), 39-45.
[http://dx.doi.org/10.1007/BF00248459] [PMID: 8717415]
[38]
Lemarie, A.; Huc, L.; Pazarentzos, E.; Mahul-Mellier, A.L.; Grimm, S. Specific disintegration of complex II succinate:ubiquinone oxidoreductase links pH changes to oxidative stress for apoptosis induction. Cell Death Differ., 2011, 18(2), 338-349.
[http://dx.doi.org/10.1038/cdd.2010.93] [PMID: 20706275]
[39]
Andreadou, I.; Papaefthimiou, M.; Zira, A.; Constantinou, M.; Sigala, F.; Skaltsounis, A.L.; Tsantili-Kakoulidou, A.; Iliodromitis, E.K.; Kremastinos, D.T.; Mikros, E. Metabonomic identification of novel biomarkers in doxorubicin cardiotoxicity and protective effect of the natural antioxidant oleuropein. NMR Biomed., 2009, 22(6), 585-592.
[http://dx.doi.org/10.1002/nbm.1370] [PMID: 19308947]
[40]
Danese, A.; Patergnani, S.; Bonora, M.; Wieckowski, M.R.; Previati, M.; Giorgi, C.; Pinton, P. Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs). Biochim. Biophys. Acta Bioenerg., 2017, 1858(8), 615-627.
[http://dx.doi.org/10.1016/j.bbabio.2017.01.003] [PMID: 28087257]
[41]
Marchi, S.; Lupini, L.; Patergnani, S.; Rimessi, A.; Missiroli, S.; Bonora, M.; Bononi, A.; Corrà, F.; Giorgi, C.; De Marchi, E.; Poletti, F.; Gafà, R.; Lanza, G.; Negrini, M.; Rizzuto, R.; Pinton, P. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr. Biol., 2013, 23(1), 58-63.
[http://dx.doi.org/10.1016/j.cub.2012.11.026] [PMID: 23246404]
[42]
Patergnani, S.; Giorgi, C.; Maniero, S.; Missiroli, S.; Maniscalco, P.; Bononi, I.; Martini, F.; Cavallesco, G.; Tognon, M.; Pinton, P. The endoplasmic reticulum mitochondrial calcium cross talk is downregulated in malignant pleural mesothelioma cells and plays a critical role in apoptosis inhibition. Oncotarget, 2015, 6(27), 23427-23444.
[http://dx.doi.org/10.18632/oncotarget.4370] [PMID: 26156019]
[43]
Lytovchenko, O.; Kunji, E.R.S. Expression and putative role of mitochondrial transport proteins in cancer. Biochim. Biophys. Acta Bioenerg., 2017, 1858(8), 641-654.
[http://dx.doi.org/10.1016/j.bbabio.2017.03.006] [PMID: 28342810]
[44]
Dodson, M.; Castro-Portuguez, R.; Zhang, D.D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol., 2019, 23, 101107.
[http://dx.doi.org/10.1016/j.redox.2019.101107] [PMID: 30692038]
[45]
Fan, Z.; Wirth, A.K.; Chen, D.; Wruck, C.J.; Rauh, M.; Buchfelder, M.; Savaskan, N. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis, 2017, 6(8), e371.
[http://dx.doi.org/10.1038/oncsis.2017.65] [PMID: 28805788]
[46]
Jang, J.Y.; Choi, Y.; Jeon, Y.K.; Aung, K.C.; Kim, C.W. Over-expression of adenine nucleotide translocase 1 (ANT1) induces apoptosis and tumor regression in vivo. BMC Cancer, 2008, 8, 160.
[http://dx.doi.org/10.1186/1471-2407-8-160] [PMID: 18522758]