Table 2.
Main data of preclinical studies conducted to evaluate cardioprotective effects of different molecules in Doxo-induced cardiotoxicity models.
| Model | Treatment | Effects | Statistical Analysis | Ref. | |
|---|---|---|---|---|---|
| Male Swiss albino mice (10 weeks of age) | Allicin (10 and 20 mg/kg) once daily for 2 weeks Doxorubicin (10 mg/kg) on the 7th, 9th, and 11th days. |
⬇AST, LDH, CK, CK-MB ⬇IL-1β, TNF-α, 8-OHdG, ⬇COX-2, caspase-3 |
⬆GSH,CAT, SOD, GPx | One-way ANOVA followed by post-hoc Duncan’s test. | [130] |
| Male Sprangue Dawley rats (220–225 g) |
Acacia hydaspica (200 and 400 mg/kg) once daily for 6 weeks Doxorubicin (3 mg/kg) single dose/week |
⬇AST, LDH, CK, CK-MB | ⬆POD,CAT, SOD, QR | One-way ANOVA followed by Tukey’s test. | [135] |
| Male C57BL/6J mice (22.5–23.5 g) | Resveratrol (20 mg/kg/day) two weeks before Doxo injection Doxorubicin (cumulative dose of 24 mg/kg) |
⬇PTGS2, ACSL4, NCOA4, ⬇p-ERK/ERK, p-p30/p38, ⬇pJNK/JNK,LDH |
⬆GSH, GPX4 | Shapiro–Wilk test and Brown–Forsythe test. Ordinary ANOVA or Welch ANOVA test. | [129] |
| H9C2 | Resveratrol (20 µM) 6 h before Doxorubicin Doxorubicin (1 µM) 24 h |
⬇p-ERK/ERK, p-38/p-38, p-JNK/JNK, ⬇LDH,PTGS2, ACSL4, NCOA4 |
⬆GSH, GPX4 | ||
| Male Sprangue Dawley rats (8 weeks) | Valsartan (20 mg/kg) daily for 6 weeks Doxorubicin (2.5 mg/kg) once per week for 6 weeks |
⬇mRNA expression levels of NOX1,NOX2, NOX4, Bax, Caspase-3, (MMP)2,MMP9, Collagen I, Beclin-1, BNP,ANP, β-MHC, GDF15, TPM1, BGN, POSTN. ⬇ALD, TNF-α, IL-6, BNP,ROS, MDA |
⬆BCL2, Collagen III ⬆SOD |
One-way or two-way ANOVA followed by Bonferroni’s post-hoc comparisons | [137] |
| H9C2 | Valsartan (5 or 10 µM) 1 h of pre-treatment Doxorubicin (1 µM) |
⬇ROS | |||
| Male C57BL/6J mice (10–12 weeks) | Rosuvastatin (100 µg/kg) 1 week before Doxorubicin and for further 2 weeks. Doxorubicin (10 mg/kg) single dose |
⬇CAT ⬇NCX1, Ryr2 |
⬆p-PLN | Unpaired Student t-test. ANOVA and the Tukey–Kramer multiple comparison post-hoc test | [125] |
| Sprangue Dawley rats | Dapagliflozin (0.1 mg/kg) per day Doxorubicin (3 mg/kg) four weekly |
⬇p-Smad3, BNP, α-SMA, p-38, ⬇NF-kB-p65, IL-8 |
One-way ANOVA followed by Bonferroni’s post-hoc comparisons | [138] | |
| H9C2 | Dapagliflozin (0–20 µM) Doxorubicin (10 µM) for 24 h |
⬇ROS, pSmad3/Smad3, ANP, BNP, α-SMA, Collagen I, Fibronectin, NF-kB-p65, IL-8 |
⬆p-AKT, HO-1, NQO1, SOD | ||
| C57BL/6J male mice | Resveratrol (10 mg/kg)+ Fibroblast growth factor-1 (0.5 mg/kg) for 7 consecutive days Doxorubicin (20 mg/kg) single injection |
⬇CK,LDH, cTnI, cleaved caspase-3 ⬇IL-1β,IL-1α, TNF-α,Mcp1, p-IKBα, p65, ROS |
⬆BCL2/BAX ratio, CAT, SOD1,SOD2, HO-1,NQO1,Sirt1 | One-way ANOVA followed by post-hoc pairwise comparisons using Tukey’s test. | [128] |
| H9C2 | Resveratrol (20 µM) Doxorubicin (1 µM) |
⬆HO-1, Nrf2 (effects were canceled by Sirt1-shRNA | |||
| C57BL/6J male mice (8 weeks) | Rutin (100 mg/kg) for 11 weeks Doxorubicin (3 mg/kg) every other day for 2 weeks starting after one week administration of Rutin |
⬇LC3 II, ATG5, P62, ⬇Caspase-3 |
⬆Akt, Bcl-2 | One-way ANOVA | [145] |
| C57BL/10 mice (10 weeks) | Fluvastatin (100 mg/kg) 4 days before Doxorubicin application Doxorubicin (20 mg/kg) for 5 days |
⬇TNF-α, ⬇Bax |
⬆SOD2.Bcl-2 | Kruskal–Wallis test in conjunction with the Mann–Whitney U post-hoc test | [123] |
| Male Swiss mice and male Sprague Dawley rats | Ginsenoside Rh2 (5 mg/kg, 10 mg/kg,20 mg/kg) total 8 doses Doxorubicin (3 mg/kg or 2 mg/kg) cumulative dose 18 mg/kg or 8 mg/kg |
⬇AST,CK,LDH, MDA |
⬆SOD, CAT, GSH | One-way ANOVA; Student t-test was performed | [131] |
| C57BL/6 mice (6–8 weeks) | Resolvin D1 (2.5 µg/kg) 30 min before Doxorubicin and every day thereafter for the duration of the experiment Doxorubicin (20 mg/kg) once |
⬇LDH,CK-MB, cTnI ⬇IL-1β,IL-6, NF-kB ⬇MDA, NOX2, NOX4, GRP78, CHOP, caspase-12,Bax, c-caspase3 |
⬆SOD,GSH, Nrf-2, OH-1,Bcl-2 | One-way ANOVA followed by Tukey’s test | [136] |
| C57BL/6J mice (8–10 weeks) | Selenium (0.2 mg/kg) 2 weeks Doxorubicin (15 mg/kg) 2 weeks |
⬇CTnI, CK, LDH ⬇IL-1β,TNF-α, IL-18, NLP3,ASC, Caspase-1 |
⬆SOD, GSH ⬆mRNA level of Nrf-2, HO-1,NQO-1, GCLM |
One-way ANOVA with Tukey’s post-hoc test | [146] |
| Male Wistar rats (250–300 g) |
Panax ginseng (5 g/kg) for 30 days Doxorubicin (2.5 mg/kg) for 2 weeks |
⬇MDA | ⬆GSHPx, SOD | One-way ANOVA followed by Scheffe’s multiple range test | [142] |
| Kunming mice | Apigenin (125 or 250 mg/kg) for 17 days Doxorubicin (3 mg/kg) cumulative dose 24 mg/kg |
⬇LDH, CK,AST ⬇Bax/Bcl-2 ratio ⬇Beclin1, LC3B II/I |
⬆PI3K/AKT/mTOR pathway | One-way ANOVA with LSD post-hoc test | [144] |
| Male Sprague Dawley rats (6–8 weeks) | Rosuvastatin (1 mg/kg) for 6 weeks Doxorubicin (1 mg/kg) for 2 weeks |
⬇AST, CK-MB ⬇HMGB1, RAGE ⬇TNF-α, IFN-γ |
⬆IL-10, IL-4 | One-way ANOVA followed by Tukey’s post-hoc test | [125] |
| BALB/c female mice | Ginsenoside Rh2 (20 mg/kg and 30 mg/kg) every day Doxorubicin (2 mg/kg) cumulative dose of 22 mg/kg |
⬇Caspase-3,Capsase-7, caspase-9 ⬇IL-1β, TNF-α, IL-6 ⬇α-SMA, Smad2, Smad3 |
⬆p 21 | One-way ANOVA followed by Tukey’s multiple comparison test | [132] |
| H9C2 HCF HUVEC |
Ginsenoside Rh2 (2.5, 5 and 10 µg/mL) 7 days after Doxorubicin treatment Doxorubicin (100 nM) for 7 days |
⬇α- SMA, Vimentin ⬇MMP2, MMP4, MMP9, MMP14, MMP17, MMP19,MMP23, MMP27, MMP28 |
|||
| H9C2 | Neferine (10 µM) Doxorubicin (1 µM) |
⬇NOX2, ROS, p-ERK, p-p38 ⬇Ca2+ intracellular accumulation ⬇COX2, TNF-α, Cytochrome c, Bax |
⬆Cyclin D1 ⬆Bcl-2 |
One-way ANOVA followed by Tukey’s multiple comparison test | [133] |
| C57Bl/6 (6 weeks) | Empagliflozin (10 mg/kg) daily for 3 days alone and then in combination with Doxorubicin Doxorubicin (2.17 mg/kg) daily for 7 days |
⬇Ferroptosis, MDA ⬇IL-1β, IL-6, IL-8, MyD88, NLRP3 ⬇MMP-9, Caspase-3 |
Non-parametric test. ANOVA test. | [139] | |
| HL-1 | Empagliflozin (50, 100 and 500 nM) Doxorubicin (0.1 to 50 µM) |
⬇intracellular Ca2+, MDA, 4-HNA, NO ⬇IL-1β, IL-6, IL-8 ⬇MyD88, NLRP2 |
|||
Abbreviations: CAT, catalase; CK, Creatine kinase; CK-MB, Creatine kinase-myocardial B fraction; GPx, Glutathione Peroxidase; GSH, Glutathione; LDH, Lactate dehydrogenase; IL-1β, Interleukin-1β; MDA, Malondialdehyde; SOD, superoxide dismutase; TNF, Tumor necrosis factor; 8-OHdG, 8-oxo-2′-deoxyguanosine; AST, Aspartate transaminase; POD, peroxidase; QR, Quinone reductase; PTGS2, prostaglandin endiperoxide synthase2; ACSL4, acyl-CoA synthetase long-chain family member; NCOA4, nuclear receptor coactivator 4; BNP, brain natriuretic peptide; ANP, atrial natriuretic peptide; (MMP)2, metallopeptidase; β-MHC, β myosin heavy chain; GDF15, growth differentiation factor 15; TPM1, tropomyosin1; BGN, biglycan; POSTN, periostin; ALD, aldosterone; NOX, NAD(P)H oxidase; NXC1, Na2+-Ca2+ exchange protein; p-PLN, phospholamban; α-SMA, α-smooth muscle actin; Mcp1, monocyte chemoattractant protein-1; cTnI, cardiac troponin I; Bcl-2, B cell lymphoma-2; Bax, BCL2-associated X; GRP78, Glucose-regulated protein 78; CHOP, C/EBP homologous protein; NLRP3, NLR family pyrin domain containing 3 protein (NRLP3) inflammasome; ASC, apoptosis-associated speck like protein containing a caspase recruitment domain; MMP, matrix metalloproteinases; MyD88, Myeloid differentiation factor-88. ⬇ denotes reduce and ⬆ denotes increase.