Table 1.
In vitro studies demonstrating the cardio-protective effects of resveratrol against anthracycline-induced cardiotoxicity.
| Study | Cell Type | DOX Treatment (Conc./Time) |
Resveratrol Treatment (Conc./Time/Time Relative to DOX) |
Finding | Proposed Mechanism |
|---|---|---|---|---|---|
| Cao Z et al. 2004 [58] | Rat cardiomyoblast H9c2 cells | 5–40 μM for 24 h | 100 μM for 72 h pre-DOX | RESV afforded marked protection against DOX-mediated cytotoxicity in H9c2 cells | ↑ Antioxidants (SOD) and Phase 2 enzymes |
| Rezk YA et al. 2006 [59] | Neonatal rat ventricular cardiomyocytes | 10 nM–100 μM | 1 μM 1 h pre-DOX | RESV reduced DOX-induced cell death | Antioxidant properties |
| Danz ED et al. 2009 [60] | Neonatal rat ventricular cardiomyocytes | 1 μM for 24 h | 10 μM for 72 h | RESV protected against DOX-induced oxidative stress and subsequent cell death | ↑ Mitochondrial function ↑ Sirt1 activation ↓ Mitochondrial ROS production ↑ SOD activity |
| Xu X et al. 2012 [61] | Neonatal rat ventricular cardiomyocytes | 1 μM for 18 h | 10 μM for 12 h pre-DOX | RESV protected against DOX-induced toxicity | ↓ DOX-induced Autophagy ↓ S6K1 activity ↓ AKT signaling ↓ mTOR signaling |
| De Angelis A et al. 2015 [62] | Human Cardiac Progenitor cells (hCPCs) | 0.5 μM for 24 h | 0.5 μM co-treatment for 24 h | RESV protected hCPCs from DOX-induced death | ↑ SIRT1 expression ↓ ROS generation ↑ SOD expression ↑ Catalase activity ↓ Apoptosis ↓ p53 acetylation |
| Lou Y et al. 2015 [63] | Rat cardiomyoblast H9c2 cells | 5 μM for 24 h | 0, 10, 25, 50 or 75 μM for 24 h followed by DOX | RESV protected H9c2 cells against DOX-induced apoptosis | ↓ ER stress marker expression ↑ Sirt1 levels |
| Gu J et al. 2016 [64] | Rat cardiomyoblast H9c2 cells | 2 μM for 24 h | 20 μM for 24 h | Co-treatment strategy with RESV attenuated the cardiotoxic effects of DOX | ↓ Apoptosis with slight ↑ in autophagy p-AMPK activation ↑ LC3 (particularly LC3-II) ↑ BCL-2 ↓ BAX expression |
| Liu MH et al. 2016 [65] | Rat cardiomyoblast H9c2 cells | 5 µM for 24 h | 25 μM for 24 h (Started 30 min pre-DOX) |
RESV protected H9c2 cells from DOX-induced apoptosis | ↓ BAX ↑ Cell viability ↑BCL-2 ↓ p53 induced-expression ↑ phosphorylation of AMPK |
| Liu MH et al. 2016 [66] | Rat cardiomyoblast H9c2 cells | 5 µM for 24 h | 25 μM for 24 h (Started 24 h pre-DOX) |
RESV protected H9c2 cells against DOX-induced apoptosis | ↑ Sirt1 activation ↑ SOD ↓ MDA expression |
| Gu J et al. 2018 [67] | Starved Rat cardiomyoblast H9c2 cells |
1 μM for 24 h | 20 μM for 24 h | RESV attenuated DOX-induced cytotoxicity | Blocking induction of E2F1/mTORC1 and E2F1/AMPKα2 pathway by DOX, leading to ↑ autophagy and ↓ apoptosis |
AKT, Protein Kinase B; AMPK, AMP-activated protein kinase; BAX, BCL (B Cell Lymphoma)-Associated X; DOX, Doxorubicin; E2F1, E2F Transcription factor 1; ER, Endoplasmic reticulum; hCPCs, Human Cardiac Progenitor cells; LC3, Light chain 3; MDA, Malonaldehyde; mTORC1, Mammalian target of Rapamycin Complex 1; RESV, Resveratrol; ROS, Reactive oxygen species; S6k1, Ribosomal protein S8 kinase beta-1; Sirt, Sirtuin; SOD, Superoxide Dismutase; ↑, increase; and ↓, decrease.