Cardioprotective Potentials of Plant‐Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

Ojha, Shreesh; Taee, Hasan Al; Goyal, Sameer N.; Mahajan, Umesh B; Patil, Chandragouda R.; Arya, Dharamvir Singh; Rajesh, Mohanraj

doi:10.1155/2016/5724973

Cited by 71 publications

(59 citation statements)

References 139 publications

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“…Inflammation, oxidative stress, and apoptosis are reported to participate in DOX-induced cardiotoxicity; 23 therefore, we subsequently investigated the protective activity of FGF21 against DOX-induced inflammation, oxidative stress, and apoptosis in the H9c2 cell line and adult mouse cardiomyocytes.…”

Section: Resultsmentioning

confidence: 99%

Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway

et al. 2017

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Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage. Treatment with FGF21 obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. Its effective anti-inflammatory activity was revealed by downregulation of inflammatory factors (tumor necrosis factor-α and interleukin-6) via the IKK/IκBα/nuclear factor-κB pathway. The anti-oxidative stress activity of FGF21 was achieved via reduced generation of reactive oxygen species through regulation of nuclear transcription factor erythroid 2-related factor 2 transcription. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, FGF21 enhanced sirtuin 1 (SIRT1) binding to liver kinase B1 (LKB1) and then decreased LKB1 acetylation, subsequently inducing AMP-activated protein kinase (AMPK) activation, which improved the cardiac inflammation, oxidative stress, and apoptosis. These alterations were significantly prohibited by SIRT1 RNAi. The present work demonstrates for the first time that FGF21 obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress, inflammation, and apoptosis through the SIRT1/LKB1/AMPK signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway

et al. 2017

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“…In parallel, quercetin protected also primary cultures of rat cardiomyocytes and H9c2 cells against the anticancer agents doxorubicin (DOX) and daunorubicin, well-known to induce acute and long-term cardiotoxicity [28][29][30][31].…”

Section: Flavonolsmentioning

confidence: 99%

Pure Polyphenols Applications for Cardiac Health and Disease

Santos

Gomes

Oudot

et al. 2018

CPD

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Polyphenols are natural compounds present in fruits and vegetables that can exert beneficial effects on human health and notably, on the cardiovascular system. Some of these compounds showed significant protective activities toward atherosclerosis, hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis as well as heart failure. Polyphenols can act through systemic effects as well as through modulation of signaling pathways such as redox signaling, inflammation, autophagy and cell death in the heart and vessels. These effects can be mediated by changes in expression level and by post-translational modifications of proteins (e.g. Stat1, CaMKII, Sirtuins, BCL-2 family members, PDEs, TRF2, eNOS and SOD). This non-comprehensive short review aims to summarize recent knowledge on the main pharmacological effects and mechanisms of cardioprotection of pure polyphenols, using different approaches such as cell culture, animal models and human studies.

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“…1,6 Accordingly, much attention is being paid to find novel antioxidant for combination regimens against the oxidative stress-triggered cardiomyopathy in DOX therapy, especially those plant-derived small molecules with considerable safety. 9 Curcumin (CUR) is a kind of natural antioxidant derived from the perennial herb Curcuma longa, and some research has highlighted its potency as an ROS scavenger. 10 Available laboratory evidence also confirmed that cardiotoxicity as a result of acute DOX exposure could be reduced by CUR supplementation both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

A complex micellar system co-delivering curcumin with doxorubicin against cardiotoxicity and tumor growth

Zhang¹,

Xu²,

Wang³

et al. 2018

IJN

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BackgroundDose-dependent irreversible cardiac toxicity of doxorubicin (DOX) becomes a major obstacle for the clinical use. Nowadays much attention is being paid to combination therapy with DOX and antioxidant agents, which would improve the clinical efficacy by protecting from cardiotoxicity along with the maintained performance as an antitumor drug. With the assistance of nanoscience and polymer engineering, herein a complex polymeric micellar system was developed for co-loading DOX and a premium natural antioxidant curcumin (CUR), and we investigated whether this new formulation for DOX delivery could achieve such a goal.MethodsThe dually loaded micelles co-encapsulating DOX and CUR (CPMDC) were prepared through thin-film rehydration by using the amphiphilic diblock copolymer monomethoxy poly(ethylene glycol) (mPEG)–poly(ε-caprolactone) (PCL)–N-t-butoxycarbonyl-phenylalanine (BP) synthesized by end-group modification of mPEG–PCL with BP. Quantitative analysis was conducted by HPLC methods for drugs in micelles or biosamples. Molecular dynamics simulation was performed using HyperChem software to illustrate interactions among copolymer and active pharmaceutical ingredients. The safety and antitumor efficacy were evaluated by in vitro viability of H9C2 cells, and tumor growth inhibition in tumor-bearing mice respectively. The protection effects against DOX-induced cardiotoxicity were investigated according to several physiological, histopathological and biochemical markers concerning systemic and cardiac toxicity.ResultsCPMDC were obtained with favorable physicochemical properties meeting the clinical demand, including uniform particle size, fairly high encapsulation efficiency and drug loadings, as well as good drug release profiles and colloidal stability. The result from molecular dynamics simulation indicated a great impact of the interactions among copolymer and small molecules on the ratiometrical co-encapsulation of both drugs. MTT assay of in vitro H9C2 cells viability demonstrated good safety of the CPMDC formulation, which also showed definite signs of decrease in xenograft tumor growth. The studies on pharmacokinetics and tissue distribution further revealed that DOX delivered by CPMDC could result in prolonged systemic circulation and increased DOX accumulation in tumor but decreased level of the toxic metabolite doxorubicinol in heart tissue compared to free DOX alone or the cocktail combination.ConclusionThe findings from present study substantiated that such a complex micellar system codelivering DOX with CUR does produce the effect of killing two birds with one stone via distinctive nanocarrier-modified drug-drug interactions.

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Cardioprotective Potentials of Plant‐Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

Cited by 71 publications

References 139 publications

Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway

Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway

Pure Polyphenols Applications for Cardiac Health and Disease

A complex micellar system co-delivering curcumin with doxorubicin against cardiotoxicity and tumor growth

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