Doxorubicin- and daunorubicin-induced energy deprivation and nucleotide degradation in isolated cardiomyocytes

Vidal, Ricardo F.; Eksborg, Staffan; Sundberg, Monica; Carlberg, Magdalena; Elfsson, Birgitta; Andersson, Bo S.

doi:10.1016/s0300-483x(96)03410-5

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…Our results do not exclude the possibility that DOX may affect other mitochondrial proteins that also influence mitochondrial respiration or MPT pore opening but they do provide a good concordance for some of the well known consequences of DOX-induced therapy in animal models, including decreased concentration of ATP in cardiac cells (Oliveira et al, 2004;Vidal et al, 1996). Concerning the inhibition of mitochondrial respiration in DOX-treated animals, other target-proteins may also be important.…”

Section: Discussionmentioning

confidence: 61%

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Oliveira

Wallace

2006

Toxicology

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Section: Discussionmentioning

confidence: 61%

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Oliveira

Wallace

2006

Toxicology

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“…DOX has been shown to inhibit sarcolemmal Na + /Ca 2+ exchange (Caroni et al, 1981) and Na + /K + pump (Shneyvays et al, 2001). In both human and animal models, DOX treatment decreased the ATP/ADP ratio (Tokarska‐Schlattner et al, 2005; Kumar et al, 2011; Octavia et al, 2012), inhibited sarcoplasmic reticulum Ca 2+ ‐ATPase (Kumar et al, 2011) and impaired Ca 2+ homeostasis (Vidal et al, 1996) resulting in a depletion of high‐energy phosphates (De Beer et al, 2001), general energy impairment (Kumar et al, 2011) with cytotoxic activity were also reported (Vidal et al, 1996). This state may reflect the depletion of high‐energy phosphates (De Beer et al, 2001) and general energy impairment (Kumar et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Gestational doxorubicin alters fetal thyroid–brain axis

Ahmed

Incerpi²

2012

Intl J of Devlp Neuroscience

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Administration of chemotherapy during pregnancy may represent a big risk factor for the developing brain, therefore we studied whether the transplacental transport of doxorubicin (DOX) may affect the development of neuroendocrine system. DOX (25 mg/kg; 3 times interaperitoneally/week) was given to pregnant rats during whole gestation period. The disturbances in neuroendocrine functions were investigated at gestation day (GD) 15 and 20 by following the maternal and fetal thyroid hormone levels, fetal nucleotides (ATP, ADP, AMP) levels and adenosine triphosphatase (Na(+), K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) activities in two brain regions, cerebrum and cerebellum. In control group, the levels of maternal and fetal serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and fetal serum growth hormone (GH) increased from days 15 to 20, whereas in the DOX group, a decrease in maternal and fetal T4, T3 and increase in TSH levels (hypothyroid status) were observed. Also, the levels of fetal GH decreased continuously from GD 15 to 20 with respect to control group. In cerebrum and cerebellum, the levels of fetal nucleotides and the activities of fetal ATPases in control group followed a synchronized course of development. The fetal hypothyroidism due to maternal administration of DOX decreased the levels of nucleotides, ATPases activities, and total adenylate, instead, the adenylate energy charge showed a trend to an increase in both brain regions at all ages tested. These alterations were dose- and age-dependent and this, in turn, may impair the nerve transmission. Finally, DOX may act as neuroendocrine disruptor causing hypothyroidism and fetal brain energetic dysfunction.

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“…It is well established that doxorubicin impairs SERCA2a-mediated calcium re-sequestration into the SR which is also an energy-requiring process. It is also known that doxorubicin leads to depletion in cellular NAD + and ATP levels [28]. Thus, it is conceivable that diminished myocardial energetic status induces enhanced calcium influx into the intracellular space through "leaky" cell membrane and/or impairs the ability of the cardiac muscle cells to re-sequester calcium.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Szenczi

Kemecsei

Holthuijsen

et al. 2005

Biochemical Pharmacology

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Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

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Doxorubicin- and daunorubicin-induced energy deprivation and nucleotide degradation in isolated cardiomyocytes

Cited by 20 publications

References 22 publications

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Gestational doxorubicin alters fetal thyroid–brain axis

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

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