Table 2.
Mechanisms of doxorubicin-induced cardiotoxicity in mouse models
| Mechanisms | Pathway/Genes | Mouse genotypes | Dosage | Ref |
|---|---|---|---|---|
| DNA damage | TOP2B | Cardiac specific-TOP2B−/− | Acute: 25 mg/kg once Chronic: 5 mg/kg/wk for 5 wk |
53 |
| Oxidative stress | MnSOD | MnSOD Tg | 10, 20 or 25 mg/kg once | 55 |
| NOX subunit | gp91 −/− | 3 mg/kg/wk for 3 wk then once at wk 5 |
56 | |
| iNOS | iNOS−/−; MnSOD Tg | 20 mg/kg once | 57, 58 | |
| NQO1 SIRT1 |
NQO1 −/− | 4 mg/kg/d × 3 d | 59 | |
| Apoptosis | p53 | p53 −/− | 20 mg/kg once | 64 |
| p53 ATM Bcl2 |
p53+/−; Bcl2 Tg | 6 mg/kg/wk for 4 wk | 65 | |
| p53 | Cardiac specific-p53−/− | 20 mg/kg once | 67 | |
| FAK p21 |
Muscle specific-FAK−/−; cardiac specific-superFAK Tg | 20 mg/kg once | 68 | |
| BAX | BAX −/− | Acute: 20 mg/kg once Chronic: 3 mg/kg × 8 over 2 wk |
71 | |
| Necrosis | BNIP3 | BNIP3 −/− | 20 mg/kg once | 70 |
| Necroptosis | RIP3 CaMKII |
RIP3 −/− | Acute: 20 mg/kg once Chronic: 5 mg/kg/wk for 4 wk |
48 |
| Ferroptosis | HFE | HFE −/− | Acute: 20 mg/kg once Chronic: 5 mg/kg × 6 at 2 wk intervals |
73 |
| ABCB8 | Cardiac specific-ABCB8−/−; cardiac specific-ABCB8 Tg | 10 mg/kg × 3 over 5 d; 6 mg/kg × 4 over 10 d |
44 | |
| NRF2 HO1 |
NRF2−/− | 20 mg/kg once | 49 | |
| GPX4 | GPX4+/−; GPX4 Tg | 6 mg/kg × 3 at 2 d intervals | 72 | |
| Autophagy | p53 mTOR |
Cardiac specific-CB7 (dominant interfering p53) Tg; cardiac specific-mTOR Tg | 10 mg/kg × 2 at 3 d interval | 66 |
| p53 Parkin |
p53−/−; Parkin−/−; Parkin Tg | 2.5 mg/kg × 5 over 2 wk | 75 | |
| Beclin1 | Beclin1+/−; cardiac specific-Beclin1 Tg | 5 mg/kg/wk for 4 wk | 79 | |
| Inflammation, Coagulation | COX-2 | Mice treated with COX-2 inhibitor | 4 mg/kg/wk for 6 wk | 81 |
| TLR2 TLR4 |
Mice treated with TLR2 or TLR4 neutralizing antibody | Acute: 10 mg/kg once Chronic: 3.5 mg/kg/wk for 8 wk |
82 | |
| PAR1 | PAR1−/− | Acute: 20 mg/kg once Chronic: 5 mg/kg/wk for 5 wk |
83 | |
| Mitochondrial damage | p53 mtDNA | p53 −/− | 20 mg/kg once | 107 |
| TOP1MT | TOP1MT −/− | 4 mg/kg/wk for 8 wk | 100 | |
| p53 STAT3 |
Cardiac specific-CB7 (dominant interfering p53); cardiac specific-STAT3−/− | 5 mg/kg/wk for 5 wk | 108 | |
| SIRT3 OGG1 |
SIRT3−/−; SIRT3 Tg | 5 mg/kg every 15 d × 3 | 103 | |
| p53 TFAM p53R2 |
p53−/−; p53 R172H knockin | 5 mg/kg/wk for 5 wk | 109 |
The genes/pathways involved in mediating anthracycline cardiotoxicity, the mouse model genotypes, and the corresponding references are shown. The dose and schedule of doxorubicin treatment used in each of the studies are also shown to better assess the chronicity of the cardiotoxicity model. ABCB8, ATP binding cassette subfamily B member 8; ATM, ataxia telangiectasia mutated kinase; BAX, Bcl2 associated x protein; Bcl2, B-cell lymphoma 2; BNIP3, Bcl2 interacting protein 3; CaMKII, calcium/calmodulin-dependent protein kinase II; COX-2, cyclooxygenase 2; FAK, focal adhesion kinase; GPX4, glutathione peroxidase 4; HFE, homeostatic iron regulator protein; HO1, heme oxygenase 1; iNOS, inducible nitric oxide synthase; MnSOD, manganese superoxide dismutase; mTOR, mammalian target of rapamycin; NOX, NAD(P)H oxidase; NRF2, nuclear factor erythroid 2-related factor 2; NQO1, NAD(P)H quinone oxidoreductase 1; OGG1, 8-oxoguanine DNA glycosylase; PAR1, protease-activated receptor 1; p53R2, p53-inducible ribonucleotide reductase; RIP3, receptor-interacting protein 3; SIRT, sirtuin; STAT3, signal transducer and activator of transcription 3; TFAM, transcription factor A, mitochondrial; TLR, toll-like receptor; TOP1MT, topoisomerase I mitochondrial; TOP2B, topoisomerase IIβ.