Table 2.
In vivo studies demonstrating the cardio-protective effect of resveratrol against anthracycline-induced cardiotoxicity.
| Study | Species/Strain | DOX Treatment (Dose/Time) |
Resveratrol Treatment (Dose/Time/Time Relative to DOX) |
Finding | Proposed Mechanism |
|---|---|---|---|---|---|
| Models of Acute Cardiotoxicity | |||||
| Wang GY et al. 2007 [68] | Adult male SD rats | A single dose of 10 mg/kg | 30, 120 mg/kg i.p. once daily for 3 days | RESV relieved DOX-induced toxic effects on the myocardium | ↓ Oxidative stress ↓ MDA and NO |
| Olukman M et al. 2009 [69] | Male Wistar rats | A single i.p dose of 20 mg/kg | 10 mg/kg/i.p. concomitant with DOX | RESV reversed DOX-induced vascular endothelial dysfunction | Prevention of excessive NO formation |
| Osman AM et al. 2013 [70] | Male Wistar rats | A single dose of 20 mg/kg | 10 mg/kg i.p. concomitant with DOX | RESV protected against DOX-induced cardiotoxicity | Antioxidant properties ↑ SOD activity |
| Pinarli FA et al. 2013 [71] | Female Wistar albino rats | A single i.p. dose of 20 mg/kg | 100 mg/kg i.p. three times weekly (first 1 week before then at weekly intervals after DOX injection) |
RESV protected against DOX-induced hemodynamic and histological changes | Antioxidant and anti-inflammatory properties |
| Al-Harthi SE et al. 2014 [72] | Male Wistar albino rats | A single dose of 20 mg/kg for 48 h | 10 mg/kg i.p. concomitant with DOX | RESV ameliorated the effect of DOX on cardiac tissue | ↓ MDA production |
| Ruan Y et al. 2015 [73] | Male C57BL/6J mice | A single i.p. dose of 20 mg/kg | 10 mg/kg/day started 3 days pre-DOX and 5 days after | RESV prevented DOX-induced cardiac dysfunction | SIRT1 Activation ↓ Apoptosis and oxidative stress Inhibit caspase-3, Bax, and p38 MAPK activation ↑ BCL-2 and SOD-1 |
| Sin TK et al. 2015 [74] | Young (2 months) and old (10 months) senescence-accelerated male mice prone 8 (SAMP8) | A single i.p. dose of 18 mg/kg | 20 mg/kg/day for 3 days (Started one day after DOX administration) |
RESV abrogated DOX-induced impairment of cardiac systolic function | Restoration of SIRT1 activity ↑ Level of p300 and ubiquitinated proteins in aged hearts. In young mice, ↓ catabolic signaling measured as acetylated Foxo1 and MuRF-1 induced by DOX |
| Gu J et al. 2016 [64] | Sprague–Dawley rats | A single i.p. dose of 15 mg/kg/day | 10 mg/kg/day i.p. | RESV treatment attenuated apoptotic cell death and decreased the cardiotoxicity of DOX | ↑ LC3 (particularly LC3-II) ↓ Cleaved caspase-3 |
| Models of Chronic Cardiotoxicity | |||||
| Rezk YA et al. 2006 [59] | Severe combined immunodeficient mice | 2 mg/kg i.v. every other day for 5 days | 3 mg/kg, i.p. started 2 h pre-DOX and 1 h after | RESV pretreatment significantly ameliorated DOX-induced bradycardia and QTc prolongation | Antioxidant properties |
| Tatlidede E et al. 2009 [75] | Both sexes Wistar albino rats |
Cumulative dose 20 mg/kg, i.p. 6 times for 2 weeks | 10 mg/kg/day, i.p. for 7 weeks | RESV alleviated DOX-induced oxidative damage of the heart | ↑ Antioxidant capacity ↓ Lipid peroxidation ↓ Neutrophil infiltration ↓ MDA level ↑ GSH level ↑ SOD and catalase activities |
| Zhang C et al. 2011 [76] | Male BALB/c Mice | 8 mg/kg i.p. at 3-week intervals (cumulative dose of 24 mg/kg) |
15 mg/kg/day (added to mouse standard chow for 7 weeks) |
RESV protected against DOX-induced cardiomyocyte apoptosis | ↑ SIRT1 expression ↓ p53 acetylation ↓ MDA levels ↓ Apoptosis ↓ Bax overexpression ↓ Cytochrome c release from mitochondria |
| Gu J et al. 2012 [77] | Male BALB/c nude Mice with induced lymphoma | Cumulative dose of 12 mg/kg, i.p. for 6 times for 2 weeks | 10 mg/kg/day, p.o. for 3 weeks; started one-week pre-DOX | RESV protected the hearts against DOX-induced apoptosis and damage | ↑ HO-1 expression and activity ↓ p53 expression ↓ Bax expression ↑ Bcl-2 expression ↓ Caspase-3 activity |
| Dudka J et al. 2012 [78] | Male albino rats of Wistar CRL: (WI)WUBR | 1 or 2 mg/kg i.p. once weekly for 7 weeks | 20 mg/kg of feed (concomitant administration, started one-week pre-DOX) |
RESV reduced the increased lipid peroxidation caused by the 1 mg DOX dose, but it slightly intensified adverse cardiac histological changes. RESV attenuated necrosis and other cardiac histopathological changes induced by the 2 mg DOX dose | ↓ Necrosis ↓ Inflammatory infiltration |
| Dolinsky VW et al. 2013 [79] | Female C57BL/6 mice | 8 mg/kg i.p. once weekly for 4 weeks | 4 g/kg diet, ad libitum concomitantly with DOX for 4 weeks |
RESV prevented DOX-induced LV remodeling and reduced DOX-induced oxidative stress | ↓ Lipid peroxidation ↑ Antioxidant defenses ↑ Mitofusin-1 and -2 expressions |
| Arafa MH et al. 2014 [80] | Adult male Wistar albino rats |
2.5 mg/kg i.p. in six injections over 2 weeks (cumulative Dose of 15 mg/kg) |
20 mg/kg Daily for 4 weeks (Started 2 weeks pre-DOX) |
RESV protected against DOX-induced cardiotoxicity and fibrosis | ↓ LV lipid peroxidation ↑ LV GSH and SOD ↓ TGF-β1 gene expression ↓ Necrosis and fibrosis |
| De Angelis A et al. 2015 [62] | Adult female Fischer 344 rats | 2.5 mg/kg i.p. for 6 times over 2 weeks (cumulative dose of 15 mg/kg) |
2.5 mg/kg concomitantly with DOX for 2 weeks + additional 4 weeks | RESV increased survival and improved cardiac function in animals with DOX-induced heart failure | ↓ CPCs apoptosis |
| Cappetta D et al. 2016 [81] | Adult female F344 rats |
2.5 mg/kg i.p. for 6 times over 2 weeks (cumulative dose of 15 mg/kg) |
2.5 mg/kg/day by oral gavage (concomitant with DOX then additional 1 week) | RESV ameliorated end-diastolic pressure/volume relationship ↓ fibrosis and fibroblast activation |
SIRT1 activation ↓ TGF-β levels ↓ p53 levels ↓ pSMAD3/SMAD3 levels ↑ Mn-SOD |
| Shoukry HS et al. 2017 [82] | Adult male Wister rats | 2.5 mg/kg i.p. for 6 times over 2 weeks (cumulative dose of 15 mg/kg) |
Prophylactic: 20 mg/kg for 6 weeks started 2 weeks with DOX then 4 weeks. Therapeutic: 20 mg/kg for 4 weeks started after DOX |
Both prophylactic and therapeutic use of RESV mitigated DOX-induced deterioration of cardiac function with the prophylactic approach being more effective than therapeutic | ↓ Myocardial apoptosis and fibrosis ↓ Bax expression ↓ NFAT3 expression |
| Matsumura N et al. 2018 [83] | Juvenile male C57BL/6 mice | 4 mg/kg i.p. once weekly for 3 weeks | 0.4% RESV in chow diet 1 week before, during, and 1 week after DOX administration | RESV normalized molecular markers of cardiotoxicity and restored the heart ability of adaptive remodeling in response to hypertension | Normalized DOX-induced cardiac p38 MAPK activation Corrected DOX-induced p53-regulated genes (p21, Igfbp3, Gadd45g, Perp) in response to AngII-induced hypertension |
| Gu J et al. 2018 [67] | Adult male C57BL/6 mice | Normal mice 4 times for 4 weeks (cumulative dose of 20 mg/kg) |
10 mg/kg i.p. prior to each DOX injection | RESV attenuated DOX-induced cardiotoxicity | RESV inhibited the E2F1/AMPKα2 and E2F1/mTORC1 pathway induced by DOX in both models |
| AMI group 5 mg/kg/day i.p. for 7 days |
10 mg/kg/day i.p. prior to each DOX injection | ||||
Akt, Protein Kinase B; AMPK, Adenosine Monophosphate-Activated Protein Kinase; AngII, Angiotensin II; Bax, BCL (B Cell Lymphoma)-Associated X; BCL, B Cell Lymphoma; CPCs, Cardiac Progenitor cells; DOX, Doxorubicin; E2F1, E2F Transcription factor 1;Foxo, forkhead box O; GSH, Glutathione; HO, Heme Oxygenase; LC3, Light chain 3; LV, left ventricular; MAPK, Mitogen-activated protein kinase; MDA, Malondialdehyde; Mn-SOD, Manganese superoxide dismutase; mTORC1, Mammalian target of Rapamycin Complex 1; MuRF-1, Muscle RING-finger protein-1; NO, Nitric oxide; NFAT3, Nuclear Factor of Activated T-Cells; PI3K, phosphatidylinositol 3-kinase; RESV, Resveratrol; SIRT1, Sirtuin 1; SOD, Superoxide Dismutase; TGF-β, transforming growth factor-β; ↑, increase; and ↓, decrease.