article · Journal of Biochemical and Molecular Toxicology
Doxorubicin is an effective chemotherapy drug, but its clinical use is often limited by cardiotoxicity. This study evaluated whether proanthocyanidin extract could offer protective effects against doxorubicin-induced cardiac injury in male rats. Animals received saline, proanthocyanidin extract alone, doxorubicin alone, or both treatments simultaneously over a four-week period. Doxorubicin administration induced marked heart injury, elevated serum damage biomarkers, triggered tissue fibrosis, and suppressed cell proliferation markers. It also provoked severe oxidative stress and inflammation while depleting endogenous antioxidant enzymes. Concurrent treatment with proanthocyanidin extract reversed these pathological alterations, normalising serum biomarkers, restoring antioxidant defences, and reducing cardiac fibrogenic proteins. The extract appeared to exert its protective effect by modulating cell cycle regulators and inhibiting the nuclear factor kappa-B signalling pathway. Consequently, the extract shows promise as a preventative agent against chemotherapy-induced heart injury.
Chemotherapy drugs like doxorubicin are crucial for cancer treatment, but their tendency to cause severe cardiac damage limits their clinical application. Identifying safe protective compounds that can shield the heart from toxic side effects could allow patients to undergo necessary chemotherapy with reduced risk of long-term cardiac complications. This work highlights a plant-derived extract that counters heart injury by limiting oxidative stress, inflammation, and fibrogenesis.
This work could inform the development of adjunct therapeutics or medical formulations designed to protect cancer patients receiving doxorubicin. Pharmaceutical companies and clinical oncology researchers would be the primary interested parties. Because the evidence is derived exclusively from a four-week study in rats, the application remains at an early laboratory stage. Extensive safety testing, formulation development, and human clinical trials will be necessary before any clinical or commercial deployment can occur.
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This study investigated the potential mechanism(s) and the signaling pathway(s) underlying the prophylactic effect of proanthocyanidin extract (PE) against doxorubicin (DOX)-induced cardiotoxicity in rats. A total of 32 male albino rats were randomly allocated into four groups. Control rats were orally administrated normal saline. Rats in the second group were orally administrated PE (50 mg/kg bw/once daily) for 4 weeks. Rats in the third group were intraperitoneally injected with DOX (10 mg/kg on Days 3, 9, 15, and 21 of the experiment). Rats in the fourth group were injected with DOX and PE simultaneously for 4 weeks. DOX significantly augmented the levels of serum heart damage biomarkers. In addition, histopathology indicated that DOX-induced cardiac tissue injury upregulated the expression of fibrogenic factors, alpha smooth muscle actin (α-SMA), transforming growth factor β1 (TGF- β1), and p16<sup>INK4A</sup> . Downregulation of cell proliferation markers, cyclin-dependent kinase-4 (CDK4), and retinoblastoma (Rb) was also observed. Furthermore, DOX-induced oxidative and inflammatory stress resulted in increased cardiac malondialdehyde (MDA), protein carbonyl (PC), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Decreased cardiac glutathione (GSH) levels and enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) were observed. Treatment of DOX-induced rat cardiotoxicity with PE normalized serum parameters for the aforementioned parameters and alleviated cardiac tissue structure. Furthermore, reduced cardiac tissue α-SMA and TGF-β1, and increased CDK4 and Rb protein expression, along with the amelioration of oxidative and inflammatory effects were observed. PE attenuates DOX-induced cardiomyocyte inflammation possibly by attenuating the nuclear factor kappa-B (NF- kB) signaling pathway. These results indicate that PE may be useful as a preventative agent against DOX-induced cardiac toxicity.
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DOI: 10.1002/jbt.22716
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