Table 1.
The effect of autophagy in DOX-induced cardiotoxicity
| Animal or cellular model | DOX dose | Treatment period | Autophagy markers | Effect on autophagy | Mechanism | Reference |
|---|---|---|---|---|---|---|
| C57BL/6 mice | 24 mg/kg (cumulative dose) | 12 days | LC3; p62; Beclin-1; Atg5 | Induction | DOX stimulates autophagy through increased ratio of LC3-II/LC3-I, and increased expression of p62, Beclin-1, and Atg5 by upregulated expression of JNK1 and p70S6K | [35] |
| C57BL/6 mice and NRCs | 21 mg/kg (cumulative dose) and 1 μM | 2 weeks and 24 h | LC3; p62; Atg5 | Induction | DOX stimulates autophagy through increased expression of LC3-II, p62, and Atg5 by reduced phosphorylation of Akt | [50] |
| C57BL/6 mice and H9c2 cells | 32 mg/kg (cumulative dose) and 10 μM | 4 weeks and 24 h | LC3; Atg5; Atg6; Atg8; Atg12 | Induction | DOX stimulates autophagy through increased expression of LC3-II, Atg5, Atg6, Atg8, and Atg12 by AMPK activation and p38 MAPK inhibition and subsequent mTOR inhibition | [49] |
| H9c2 cells | 5 μg/ml | 24 h | LC3; p62; Beclin-1 | Induction | DOX stimulates autophagy through increased expression of LC3-II and Beclin-1 and decreased expression of p62 | [51] |
| NRCs | 1 μM | 18 h | LC3; p62; Atg5; Atg12-Atg5 complex | Induction | DOX stimulates autophagy through increased expression of Atg5 and Atg12-Atg5 complex and decreased expression of p62 by upregulation of p70S6K expression | [52] |
| NRCs | 1 μM | 18 h | LC3; p62; Beclin-1; Atg5; Atg7; Atg12 | Induction | DOX stimulates autophagy through increased expression of LC3-II, Beclin-1, Atg5, Atg7, and Atg12 and decreased expression of p62 by depleting GATA4 protein levels | [53] |
| C57BL/6 mice and H9c2 cells | 20 mg/kg (cumulative dose) and 1 μM | 4 weeks and 24 h | LC3; p62; Beclin-1; LAMP1 | Inhibition | DOX inhibits autophagy through suppression of Beclin-1/LAMP1 pathway | [10] |
| C57BL/6 mice | 15 mg/kg (single dose) | 3 days | Beclin-1 | Inhibition | DOX inhibits autophagy through decreased Beclin-1 by inhibition of AMPK and activation of mTOR | [54] |
| C57BL/6 mice and H9c2 cells | 20 mg/kg (cumulative dose) and 1 μM | 4 weeks and 24 h | LC3 | Inhibition | DOX inhibits autophagy through decreased ratio of LC3-II/LC3-I by activating E2F1/mTORC1 pathway | [46] |
| GFP-LC3 transgenic mice and H9c2 cells | 20 mg/kg (cumulative dose) and 3 μM | 15 days and 24 h | LC3; p62 | Inhibition | DOX inhibits autophagy as shown in the accumulation of LC3-I and p62 | [55] |
| GFP-LC3 transgenic mice and neonatal mice cardiomyocytes | 20 mg/kg (cumulative dose) and 0.1 μM | 5 days and 6 h | LC3; p62 | Inhibition | DOX inhibits autophagy through decreased expression of AMPK and ULK1 | [56] |
DOX doxorubicin, H9c2 cells rat cardiomyocyte cell line, NRCs neonatal rat ventricular cardiomyocytes, LC3 microtubule-associated proteins 1A/1B light chain 3, Atg autophagy-related, LAMP1 lysosomal-associated membrane proteins 1, JNK1 c-JUN NH2-terminal kinase 1, p70S6K p70S6 kinase, Akt protein kinase B, AMPK AMP-activated protein kinase, MAPK mitogen-activated protein kinase, mTORC1 mammalian target of rapamycin complex 1, E2F1 E2F transcription factor 1, ULK1 Unc-51 like autophagy activating kinase 1