Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin

Mimnaugh, Edward G.; Trush, Michael A.; Bhatnagar, M.C.; Gram, Theodore E.

doi:10.1016/0006-2952(85)90766-x

Cited by 143 publications

(45 citation statements)

References 58 publications

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“…14 Additional indications of oxidative injury to mitochondria include membrane lipid peroxidation, 15 inhibition of respiration and oxidative phosphorylation, decreased mitochondrial ATPase activity, and a net decrease in the redox state of respiratory carriers. 16 Recently, ADR treatment has been shown to activate the renin angiotensin system.…”

Section: Introductionmentioning

confidence: 99%

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

et al. 2014

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Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p50.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p50.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p50.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo. KeywordsAdriamycin-induced nephrotoxicity, Aliskren, captopril, mitochondrial ATP, mitochondrial membrane potential, oxidative stress index History

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Section: Introductionmentioning

confidence: 99%

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

et al. 2014

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“…The secondarily derived hydroxyl radicals can cause protein and DNA damage and initiate lipid peroxidation (5). Increased lipid peroxidation, and enhanced free radical generation in the heart have been demonstrated after administration of ADR (1)(2)(3)(4)(6)(7)(8). However, whether free radicals generated by ADR are responsible for the cardiac toxicity is not certain because of difficulties in interpreting results obtained from studies using exogenous antioxidants (4).…”

Section: Introductionmentioning

confidence: 99%

The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice.

Yen¹,

Oberley²,

et al. 1996

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Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury. ( J. Clin. Invest. 1996. 98:1253-1260.) Key words: free radicals • mitochondria • antioxidants • heart • antineoplastic agents

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“…Some mitochondrial hypothesis to explain the cardiac toxicity of DOX have been proposed: oxidative stress associated with the DOX redox-cycling, mitochondrial damage and consequent deterioration of myocardial energy, deregulation of mitochondrial and cellular Ca 2+ homeostasis and disruption of mitochondrial gene expression [125]. Biochemical and physiological data strongly suggests that DOX is primarily toxic to the heart muscle through increased formation of ROS [126], which oxidizes proteins [127], nucleic acids [128] and stimulates lipid peroxidation [129], thus altering the integrity of the cell membrane [126,[130][131][132]. Data from the literature indicates that cardiac mitochondria are especially damaged by DOX-induced oxidative stress [118,[133][134][135]; in fact, the cardiac tissue is particularly susceptible to ROS due to reduced levels of enzymatic antioxidants defenses when compared with other tissues [118].. DOXinduced oxidative stress can also be part of the mechanism of increased MPT which has been implicated in mitochondrial and cell dysfunction induced by DOX [136][137][138][139][140][141].…”

Section: Mitochondrial Cardiovascular Toxicitymentioning

confidence: 99%

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

Pereira¹,

Moreira²,

Pereira³

et al. 2009

CDS

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Mitochondria are recognized as the producers of the majority of energy cells need for their normal activity. After the initial comprehension of how mitochondrial oxidative phosphorylation produces energy, mitochondrial research was not a priority for most cell biologists until novel mitochondrial functions were identified. In fact, it is now known that mitochondria are not only involved in cell calcium homeostasis, intermediate metabolism and free radical generation but are also a crucial crossroad for several cell death pathways. The notion that several clinically used drugs and other xenobiotics induce organ degeneration through damaging mitochondrial bioenergetics led to the use of the organelle as an effective and reliable bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide range of compounds on isolated mitochondrial fractions were later replaced by novel high-throughput methods to investigate the safety of a very large number of new molecules. Without surprise, the assessment of "mitochondrial safety" for new discovered molecules is of clear interest for pharmaceutical companies which can now select compounds lacking mitochondrial toxicity to undergo further trials, thus avoiding the possibility of later human toxicity due to mitochondrial liabilities.

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Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin

Cited by 143 publications

References 58 publications

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice.

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

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