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Doxorubicin, an anthracycline from Streptomyces peucetius , exhibits antitumor activity against various cancers. However, doxorubicin is cardiotoxic at cumulative doses, causing increases in intracellular reactive oxygen species in the heart. Spinochrome D (SpD) has a structure of 2,3,5,6,8-pentahydroxy-1,4-naphthoquinone and is a structural analogue of well-known sea urchin pigment echinochrome A. We previously reported that echinochrome A is cardioprotective against doxorubicin toxicity. In the present study, we assessed the cardioprotective effects of SpD against doxorubicin and determined the underlying mechanism. ¹H-NMR-based metabolomics and mass spectrometry-based proteomics were utilized to characterize the metabolites and proteins induced by SpD in a human cardiomyocyte cell line (AC16) and human breast cancer cell line (MCF-7). Multivariate analyses identified 12 discriminating metabolites (variable importance in projection > 1.0) and 1814 proteins from SpD-treated AC16 cells. Proteomics and metabolomics analyses showed that glutathione metabolism was significantly influenced by SpD treatment in AC16 cells. SpD treatment increased ATP production and the oxygen consumption rate in D-galactose-treated AC16 cells. SpD protected AC16 cells from doxorubicin cytotoxicity, but it did not affect the anticancer properties. With SpD treatment, the mitochondrial membrane potential and mitochondrial calcium localization were significantly different between cardiomyocytes and cancer cell lines. Our findings suggest that SpD could be cardioprotective against the cytotoxicity of doxorubicin.

Background: The protective effects of metformin (Met) against doxorubicin (Dox)-induced cardiotoxicity via potential hypotheses of mechanisms of action with unknown reliability and credibility. Objectives: This study aimed to investigate the protective effects of Met against Dox-induced cardiotoxicity and the underlying mechanisms of action, as well as examine their reliability and credibility. Methods: A comprehensive search was conducted within the PubMed, Embase, Web of Science, Science Direct, Scopus, and CNKI databases from inception to 31 December 2023. Animal experiments evaluating the efficacy of Met against Dox-induced cardiotoxicity were included in this study. The primary efficacy outcomes were markers of myocardial injury. Effect size was measured using the standardized mean difference for continuous variables. Data were pooled using a random-effects model in the Stata 18 statistical software package. Results: Twenty-one studies involving 203-208 animals treated with Dox and 271-276 animals treated with Dox and Met were included in this analysis. Quality assessment revealed high-quality scores. Pooled results favored Met treatment based on the serum lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), and aspartate aminotransferase levels. Sensitivity analysis using the leave-one-out method demonstrated stable results. Funnel plots, Egger's test, and Begg's test confirmed potential publication bias. The oxidative stress hypothesis has been investigated extensively based on abundant evidence. Conclusion: Met is effective and safe for protecting against Dox-induced cardiotoxicity, thus making it an appropriate drug for clinical investigation. The oxidative stress hypothesis of mechanism of action is well established with highest reliability and credibility. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its clinical application is greatly limited because of the cardiotoxicity. Thus, exploration of effective therapies against DOX-induced cardiotoxicity is necessary. The aim of this study is to investigate the effects and possible mechanisms of Trametes Sanguinea Lyoyd fermented crude polysaccharide (TSLFACP) against DOX-induced cardiotoxicity. We investigated the protective effects of TSLFACP on myocardial injury and its possible mechanisms using two in vitro cells of DOX-treated cardiomyocytes H9C2 and embryonic myocardial cell line CCC-HEH-2 and a in vivo mouse model of DOX-induced myocardial injury. We found that TSLFACP could reverse DOX-induced toxicity in H9C2 and CCC-HEH-2 cells. Similarly, we found that when pretreatment with TSLFACP (200 mg/kg, i.g.) daily for 6 days, DOX-induced myocardial damage was attenuated, including the decrease in serum myocardial injury index, and the amelioration in cardiac histopathological morphology. Additionally, immunohistochemistry and western blotting were used to identify the underlying and possible signal pathways. We found that TSLFACP attenuated the expression of LC3-II, Beclin-1 and PRAP induced by DOX. In conclusion, our results demonstrated that TSLFACP could protect against DOX-induced cardiotoxicity by inhibiting autophagy and apoptosis. [ABSTRACT FROM AUTHOR]

Backgrounds: Echinochrome A (6-ethyl-2,3,5,7,8-pen-tahydroxy-1,4-naphthoquinone) is a common naphthoquinone pigment found in the shells, spines, and coelomic fluid of sea urchins. We previously reported that echinochrome A has a cardioprotective function as an antioxidant against reactive oxygen species (ROS) induced by tert-Butyl hydroperoxide and doxorubicin. Methods: In the current study, we evaluated the antioxidant activity, ATP production, and oxygen consumption rate (OCR) of seven echinochrome structural analogs (spinochromes) in AC16 human cardiomyocyte cells. The compounds included in the study had various substituents including hydroxyl (Sp B and Sp E), amino (Echm A), methoxyl (TriMeEch A), pentyl (No. 284), and hydroxypentyl (No. 285). We also investigated the effects of one dimeric spinochrome (Binaphthoquinone). Results: Spinochromes exhibited enhanced antioxidant activity and ATP production. Interestingly, the hydroxylated compounds significantly enhanced the OCR and had a cardiomyocyte protective effect in the presence of doxorubicin. Conclusion: Our findings indicate that echinochrome A structural analogs may have therapeutic potential for cardio-protection. [ABSTRACT FROM AUTHOR]

UTL-5g is a small-molecule TNF-α modulator that is anti-inflammatory in a carrageenan-induced edema animal model and chemoprotective against anticancer drug-induced side effects. Recently, it was shown that UTL-5g is a prodrug and its active metabolite is 5-methylisoxazole-3-carboxylic acid (Isox). We set out to investigate the anti-inflammatory and cardioprotective effects of Isox, and two of its esterified analogues, methyl ester (Isox-Me), and ethyl ester (Isox-Et). First, the carrageenan-induced edema animal model was employed to compare their anti-inflammatory effects. Briefly, Wistar rats were randomly divided into 5 groups and pretreated with vehicle, leflunomide, Isox, Isox-Me, and Isox-Et respectively before carrageenan treatment. The results showed that the anti-inflammatory effect of Isox was essentially the same as that of leflunomide. However, the anti-inflammatory effects of Isox-Me and Isox-Et were lower than that of Isox. In the second study, cardioprotective effects of Isox, Isox-Me, and Isox-Et on doxorubicin (DOX)-induced toxicity were investigated. SD rats were randomly divided into five groups. Rats in groups 1 and 2 were pretreated with vehicle; rats in groups 3-5 were pretreated with Isox, Isox-Me, and Isox-Et respectively for 5 consecutive days. One hr after the last treatment, animals in group 2-5 were treated with DOX. Twenty four hr later, effects of test compounds on cardioprotection were examined. The results showed that Isox significantly reduced the cardiotoxicity, but Isox-Me and Isox-Et did not show much cardioprotective effect. A subsequent in vitro MTT study confirmed that Isox, but not Isox-Me or Isox-Et, protected cardiomyocytes from the injury induced by DOX. In summary, Isox is anti-inflammatory against carrageenan-induced edema and the anti-inflammatory effect of Isox is at least partially responsible for its chemoprotective effect against DOX-induced cardiac injury; esterification of Isox significantly reduces its anti-inflammatory effect and cardioprotective effect. [ABSTRACT FROM AUTHOR]

Doxorubicin, an anthracycline from Streptomyces peucetius, exhibits antitumor activity against various cancers. However, doxorubicin is cardiotoxic at cumulative doses, causing increases in intracellular reactive oxygen species in the heart. Spinochrome D (SpD) has a structure of 2,3,5,6,8-pentahydroxy-1,4-naphthoquinone and is a structural analogue of well-known sea urchin pigment echinochrome A. We previously reported that echinochrome A is cardioprotective against doxorubicin toxicity. In the present study, we assessed the cardioprotective effects of SpD against doxorubicin and determined the underlying mechanism. 1H-NMR-based metabolomics and mass spectrometry-based proteomics were utilized to characterize the metabolites and proteins induced by SpD in a human cardiomyocyte cell line (AC16) and human breast cancer cell line (MCF-7). Multivariate analyses identified 12 discriminating metabolites (variable importance in projection > 1.0) and 1814 proteins from SpD-treated AC16 cells. Proteomics and metabolomics analyses showed that glutathione metabolism was significantly influenced by SpD treatment in AC16 cells. SpD treatment increased ATP production and the oxygen consumption rate in D-galactose-treated AC16 cells. SpD protected AC16 cells from doxorubicin cytotoxicity, but it did not affect the anticancer properties. With SpD treatment, the mitochondrial membrane potential and mitochondrial calcium localization were significantly different between cardiomyocytes and cancer cell lines. Our findings suggest that SpD could be cardioprotective against the cytotoxicity of doxorubicin. [ABSTRACT FROM AUTHOR]