Lipid Emulsion Inhibits the Late Apoptosis/Cardiotoxicity Induced by Doxorubicin in Rat Cardiomyoblasts

Subbarao, Raghavendra Baregundi; Ok, Seong-Ho; Kang, Dawon; Kim, Eun Jin; Kim, Ji-Yoon; Sohn, Ju-Tae

doi:10.3390/cells7100144

Cited by 20 publications

(30 citation statements)

References 39 publications

(87 reference statements)

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“…In a clinical setting, Zhao and Zhang (2017) demonstrated that Dox administration activated cell death pathways in the hearts of cancer patients within hours of intravenous administration. Likewise, Subbarao and colleagues (2018) reported that H9c2 cardiomyoblasts treated with Dox had a significant increase in late apoptotic cells. Accordingly, our findings revealed that chronic Dox exposure significantly accelerates the rate of apoptosis in the cardiac and breast cancer cells.…”

Section: Discussionmentioning

confidence: 92%

“…Although a direct link between antioxidants and the modulation of cancer immunoediting has not been fully established, evidence suggests that flavonoids may be able to modulate immunoediting processes like restoring cancer immune surveillance which may be helpful in eradicating cancer cells ( Bhattacharyya et al., 2010 ; Bose et al., 2015 ). Additionally, such flavonoids have been demonstrated to play a crucial role in mitigating the cardiotoxic effects inferred by Dox administration ( Bast et al., 2007 ; Sun et al., 2007 ; Chang et al., 2019 ). In the case of Pin, its ability to regulate inflammatory cytokines, improve mitochondrial function whilst inhibiting platelet aggregation and mitigating apoptosis in the cardiac muscle makes it a suitable candidate in the prevention of Dox-induced cardiotoxicity ( Saad et al, 2015 ; Shen, 2019).…”

Section: Introductionmentioning

confidence: 99%

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The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

et al. 2020

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Background The clinical use of Doxorubicin (Dox) is significantly limited by its dose-dependent cardiotoxic side effect. Accumulative evidence suggests that the use of flavonoids, such as the antioxidative Pinocembrin (Pin), could be effective in the prevention of Dox-induced cardiotoxicity. Accordingly, we investigated the ability of pinocembrin (Pin) to attenuate Dox-induced cardiotoxicity in an in vitro H9c2 cardiomyoblast model. Methodology The cardioprotective potential of Pin was established in H9c2 cells. Here, cells were treated with Dox (2μM), Dox (2μM) + Pin (1μM), and Dox (2μM) + Dexrazoxane (20μM) for 6 days. Thereafter, the safe co-administration of Pin with Dox, in a cancer environment, was investigated in MCF-7 breast cancer cells subjected to the same experimental conditions. Untreated cells served as the control. Subsequently, Pin’s ability to attenuate Dox-mediated oxidative stress, impaired mitochondrial bioenergetics and potential, as well as aggravated apoptosis was quantified using biochemical assays. Results The results demonstrated that co-treatment with Pin mitigates Dox-induced oxidative stress by alleviating the antioxidant enzyme activity of the H9c2 cells. Pin further reduced the rate of apoptosis and necrosis inferred by Dox by improving mitochondrial bioenergetics. Interestingly, Pin did not decrease the efficacy of Dox but, rather increased the rate of apoptosis and necrosis in Dox-treated MCF-7 cells. Conclusion The findings presented in this study showed, for the first time, that Pin attenuates Dox-induced cardiotoxicity without reducing its chemotherapeutic effect. We propose that additional studies, using in vivo models, should be conducted to further investigate Pin as a suitable candidate in the prevention of the cardiovascular dysfunction inferred by Dox administration.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

et al. 2020

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“…Human umbilical vein endothelial cells (HUVECs, EA.hy926 cells, American Type Culture Collection, Manassas, VA, USA) were cultured in Dulbecco's modified Eagle's medium (HyClone, GE Healthcare, UT, USA) supplemented with 10% heat-inactivated fetal bovine serum (Gibco, Life Technologies, NY, USA), 2 mM l-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin as previously described [20,21]. Cells were plated in a 100-mm culture dish and incubated at 37°C in a humidified atmosphere containing 5% CO2.…”

Section: Cell Culturementioning

confidence: 99%

“…Western blot analysis was carried out as described previously [18,19,21]. Cytosolic and membrane fractions were isolated from cells using a Mem-PER ® eukaryotic membrane protein extraction reagent kit (ThermoFisher Scientific, MA, USA) according to the manufacturer's instructions.…”

Section: Western Blot Analysismentioning

confidence: 99%

Nitric oxide-mediated inhibition of phenylephrine-induced contraction in response to hypothermia is partially modulated by endothelial Rho-kinase

Lee

Kim

et al. 2020

Int. J. Med. Sci.

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This study examined the possible upstream cellular signaling pathway associated with nitric oxide (NO)-mediated inhibition of phenylephrine-induced contraction in isolated rat aortae in response to mild hypothermia, with a particular focus on endothelial Rho-kinase. We examined the effects of mild hypothermia (33°C), wortmannin, N ω -nitro-L-arginine methyl ester (L-NAME), Y-27632, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue, alone and combined, on phenylephrine-induced contraction in isolated rat aortae. Finally, we examined the effects of mild hypothermia, wortmannin, Y-27632 and L-NAME, alone and combined, on endothelial nitric oxide synthase (eNOS) and endothelial Rho-kinase membrane translocation induced by phenylephrine. Mild hypothermia attenuated phenylephrine-induced contraction only in endothelium-intact aortae. L-NAME, wortmannin, ODQ and methylene blue increased phenylephrine-induced contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin did not significantly alter the L-NAME-induced enhancement of phenylephrine-induced maximal contraction of endotheliumintact aortae pretreated at 33°C. Wortmannin abolished the ability of Y-27632 to magnify the hypothermic inhibition of maximal phenylephrine-induced contraction. Wortmannin and L-NAME inhibited the enhancing effect of mild hypothermia on phenylephrine-induced eNOS phosphorylation. Y-27632 and L-NAME attenuated the enhancing effect of hypothermia on phenylephrine-induced endothelial Rho-kinase membrane translocation. The results suggest that hypothermia-induced, NO-dependent inhibition of phenylephrine-induced contraction is mediated by phosphoinositide 3-kinase and inhibited by endothelial Rho-kinase activation.

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“…LE is well-known as a nonspecific antidote in medicine, in particular for bupivacaine-induced cardiotoxicity [6]. LE accelerates recovery from bupivacaine toxicity in isolated rat heart [7], inhibits apoptosis and cardiotoxicity induced by bupivacaine or doxorubicin in rat cardiomyoblasts [8,9], reduces bupivacaine content, and increases cardiac bupivacaine washout [7,10]. The protective mechanisms of LE on bupivacaine-induced cardiotoxicity have been generally thought to be lipid sink, lipid shuttle, fatty acid supply, reversal of mitochondrial dysfunction and cardiac Na + channel blockade, inhibition of nitric oxide release, and inotropic effects [11].…”

Section: Introductionmentioning

confidence: 99%

Involvement of TREK-1 Channel in Cell Viability of H9c2 Rat Cardiomyoblasts Affected by Bupivacaine and Lipid Emulsion

Yang

Siregar

Kim

et al. 2019

Cells

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Lipid emulsion (LE) therapy has been used to reduce overdose of bupivacaine (BPV)-induced cardiotoxicity. The TWIK-related potassium channel-1 (TREK-1) is inhibited by BPV and activated by polyunsaturated fatty acids, which are the main component in LE. These pharmacological properties inspired us to investigate whether the TREK-1 channel is associated with cell viability of H9c2 cardiomyoblasts affected by BPV and LE. Consistent with previous studies, BPV-induced cell death was reduced by LE treatment. The reduction in the TREK-1 expression level by BPV was alleviated by LE. The BPV cytotoxicity highly decreased in TREK-1 overexpressed cells but was the opposite in TREK-1 knocked-down cells. TREK-1 channel activators and inhibitors increased and decreased cell viability, respectively. BPV-induced depolarization of the plasma and mitochondrial membrane potential and increase in intracellular Ca2+ level were blocked by LE treatment. BPV-induced depolarization of membrane potential was reduced in TREK-1 overexpressed cells, indicating that TREK-1 channels mediate setting the resting membrane potentials as a background K+ channel in H9c2 cells. These results show that TREK-1 activity is involved in the BPV cytotoxicity and the antagonistic effect of LE in H9c2 cells and suggest that TREK-1 could be a target for action of BPV and LE.

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Lipid Emulsion Inhibits the Late Apoptosis/Cardiotoxicity Induced by Doxorubicin in Rat Cardiomyoblasts

Cited by 20 publications

References 39 publications

The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

Nitric oxide-mediated inhibition of phenylephrine-induced contraction in response to hypothermia is partially modulated by endothelial Rho-kinase

Involvement of TREK-1 Channel in Cell Viability of H9c2 Rat Cardiomyoblasts Affected by Bupivacaine and Lipid Emulsion

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