Doxorubicin directly binds to the cardiac-type ryanodine receptor

Saeki, Kazuhiko; Obi, Ichiro; Ogiku, Noriko; Shigekawa, Munekazu; Imagawa, Toshiaki; Matsumoto, Takeshi

doi:10.1016/s0024-3205(02)01524-2

Cited by 57 publications

(45 citation statements)

References 19 publications

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“…3 H]ryanodine binding to the RyR, and the increased RyR channel open probability (Pessah et al, 1990;Saeki et al, 2002). These observations indicate that doxorubicin alters RyR function, and not necessarily protein content, which is in agreement with our finding that doxorubicin did not affect RyR protein expression [but contrasted with the decrease in RyR protein expression in rabbit hearts (Olson et al, 2005)].…”

Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onsupporting

confidence: 90%

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administrationapproved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptoticinducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicininduced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 M, 24 h) prevented doxorubicin (0.5 M, 24 h)-induced elevation of diastolic [Ca 2ϩ ] i , the slowing of [Ca 2ϩ ] i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca 2ϩ ) ATPase, Na ϩ /Ca 2ϩ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/ dt max ) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.

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Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onsupporting

confidence: 90%

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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“…In addition, quinone-containing compounds such as DOX, 1,4-benzoquinone, and 1,4-naphtoquinone are shown to open RyR by oxidizing essential thiols in RyR (Feng et al, 1999). Direct binding of DOX to RyR has also been reported (Saeki et al, 2002). Similarly, with the isolated SR preparation, DOX increased ryanodine binding to the receptor in a dose-dependent manner, indicating an increase of high affinity state of RyR for ryanodine.…”

Section: Discussionmentioning

confidence: 57%

“…A previous study has reported that DOX binds directly to RyR, thereby increases open probability (Saeki et al, 2002) and that DOX-induced Ca 2+ increase shows a similar pattern of RyR-mediated Ca 2+ signal (Kim et al, 1989). The above data also suggest that DOX induces Ca 2+ release from SR. An involvement of RyR in Ca 2+ release was examined using SR preparations from rat hearts.…”

Section: Dox Induces Ca 2+ Release From Isolated Srmentioning

confidence: 90%

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Kim

Kim²,

Kim³

et al. 2006

Exp Mol Med

236

134

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“…This calcium overload may contribute to impaired contractile function by promoting release of the proapoptotic factor cytochrome c and/or activating the cysteine protease calpain. Calpains initiate turnover of both regulatory and structural myofibrillar proteins through cleavage and release of large polypeptide fragments [34][35][36]. DOX is also known to significantly degrade the structural protein titin in cardiomyocytes in concert with impaired relaxation [37].…”

Section: ) Ultrastructural Changes To Myocytes: Rosmentioning

confidence: 99%

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

Kouzi

Uddin

2016

J Pharm Pharm Sci

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Doxorubicin is one of the most commonly used cytotoxic anticancer drugs against several cancers. Although a highly effective anticancer drug, the clinical use of doxorubicin is severely limited by its cardiotoxicity which results in morbidity, poor quality of life, and premature mortality. Only very few clinically accepted methods to minimize doxorubicin-induced cardiac injury are available today, but none of them have proven to be completely successful. Due to limited alternative strategies, a number of potential cardioprotective therapies are currently being investigated for treating and/or preventing doxorubicin-induced cardiotoxicity. Of these potential strategies, aerobic exercise training is the only nonpharmacologic strategy that shows a great deal of promise. Although there are no published human clinical trials, evidence from numerous animal studies suggests that aerobic exercise training, administered prior to, during and/or following doxorubicin therapy, is protective against doxorubicin-induced cardiac injury. Protective properties of exercise training against the cardiotoxicity of doxorubicin have been attributed to a number of potential molecular mechanisms including: enhancing the production of endogenous antioxidant machineries; regulating proapoptotic signaling; stimulating the release, mobilization and homing of cardiac progenitor cells; limiting myocyte turnover; eliciting favorable adaptations in myocardial calcium handling and preventing calcium overload; modulating cardiac AMPK activity; downregulating cardiac autophagy/lysosomal signaling; and reducing myocardial doxorubicin accumulation. Further preclinical and clinical research is needed to decipher and refine the molecular mechanisms underlying the cardioprotective effects of exercise training, as well as to define the nature and magnitude of the effect of exercise on doxorubicin-induced cardiotoxicity in cancer patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Doxorubicin directly binds to the cardiac-type ryanodine receptor

Cited by 57 publications

References 19 publications

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

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