Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway.

BACKGROUND: Doxorubicin (DOX) is a potent anticancer medication, but its significant cardiotoxicity poses a challenge in clinical practice. Galangin (Gal), a flavonoid compound with diverse pharmacological activities, has shown potential in exerting cardioprotective effects. However, the related molecular mechanism has not been fully elucidated. PURPOSE: Combined with bioinformatics and experimental verification methods to investigate Gal's potential role and underlying mechanisms in mitigating DOX-induced cardiotoxicity (DIC). METHODS: C57BL/6 mice received a single dose of DOX via intraperitoneal injection 4 days before the end of the gavage period with Gal. Myocardial injury was evaluated using echocardiography, myocardial injury biomarkers, Sirius Red and H&E staining. H9c2 cells were stimulated with DOX to mimic DIC in vitro. The potential therapeutic target of Gal was identified through network pharmacology, molecular docking and cellular thermal shift assay (CETSA), complemented by an in-depth exploration of the GSTP1/JNK signaling pathway using immunofluorescence. Subsequently, the GSTP1 inhibitor Ezatiostat (Eza) substantiated the signaling pathway. RESULTS: Gal administration considerably raised DOX-inhibited the left ventricular ejection fractions (LVEF), reduced levels of myocardial injury markers (c-TnI, c-TnT, CKMB, LDH, and AST), and alleviated DOX-induced myocardial histopathological injury and fibrosis in mice, thereby improving cardiac dysfunction. The ferroptosis induced by DOX was inhibited by Gal treatment. Gal remarkably ameliorated the DOX-induced lipid peroxidation, accumulation of iron and Ptgs2 expression both in H9c2 cells and cardiac tissue. Furthermore, Gal effectively rescued the DOX-inhibited crucial regulators of ferroptosis such as Gpx4, Nrf2, Fpn, and Slc7a11. The mechanistic investigations revealed that Glutathione S-transferase P1 (GSTP1) may be a potential target for Gal in attenuating DIC. Gal act on GSTP1 by stimulating its expression, thereby enhancing the interaction between GSTP1 and c-Jun N-terminal kinase (JNK), leading to the deactivation of JNK/c-Jun pathway. Furthermore, interference of GSTP1 with inhibitor Eza abrogated the cardioprotective and anti-ferroptotic effects of Gal, as evidenced by decreased cell viability, reduced expression of GSTP1 and Gpx4, elevated MDA levels, and promoted phosphorylation of JNK and c-Jun compared with Gal treatment. CONCLUSION: Gal could inhibit ferroptosis and protect against DIC through regulating the GSTP1/JNK pathway. Our research has identified a novel pathway through which Gal regulates DIC, providing valuable insights into the potential therapeutic efficacy of Gal in mitigating cardiotoxic effects.

"The protective effect of nano curcumin supplementation on doxorubicin induced cardiotoxicity in breast cancer patients; a randomized, double-blind clinical trial".

BACKGROUND: Anthracycline drugs play a fundamental role in breast cancer treatment; however, the cardiotoxicity side effects obscure the advantages of treatment. Curcumin has antioxidant and anti-inflammatory effects. MATERIALS AND METHODS: In this study, we investigated the effect of nanocurcumin supplementation on Doxorubicin induced Cardiotoxicity. In this randomized clinical trial, a week before starting the doxorubicin regimen for breast cancer patients, the control group received placebo and curcumin group received 80 mg daily dosage of nano curcumin capsules for six months. Echocardiography parameter changes before chemotherapy and after six months were evaluated. RESULTS: 46 patients were included. Left ventricle (LV) ejection fraction significantly decreased and LV end diastolic volume significantly increased in control group but no significant changes were observed in the curcumin group (LVEF: 2.62 ± 59.35 to 4.23 ± 56.85, p-value: 0.014 vs 59.55 ± 1.91 to 58.46 ± 3.41, p-value:0.135; LVEDV: 77.09 ± 15.33 to 80.65 ± 14.54, p-value:0.023 vs 72.41 ± 15.34 74.00 ± 14.25, p-value: 0.294). Additionally, LVEF, LV end systolic diameter (LVESD), and end diastolic diameter (LVEDD) insignificantly more decreased in control group versus curcumin group (LVEF: 4.13 ± 2.50- vs 3.36 ± 1.08-, p-value: 0.223; LVESD: 0.27 ± 0.06-vs 0.120.45 ±, p-value:0.110; LVEDD: -0.44 ± 0.33 vs 0.070.33 ±, p-value:0.269). Furthermore, symptomatic cardiomyopathy and ejection fraction ratio less than 53% were not observed. The LVEF reduction >15% was observed was also high in the control group, (p-value = 0.020). CONCLUSION: This study shows the possible effect of nanocurcumin capsules to reduce the cardiotoxicity of anthracycline chemotherapy medications.

LC-MS/MS method for simultaneous Doxorubicin and Baicalein estimation: formulation and pharmacokinetic applications.

Aim & objective: Combinatorial delivery of Doxorubicin (DOX) and Baicalein (BAC) has a potential to improve breast cancer treatment by mitigating the cardiotoxicity induced by DOX. The nanoformulation has been optimized and subjected to pharmacokinetic studies using LC-MS/MS.Materials & methods: Nanoformulation bearing DOX and BAC was optimized using quality by design approach and method validation was done following USFDA guidelines.Results: The particle size, PDI and zeta potential of developed nanoformulation were 162.56 ± 2.21 nm, 0.102 ± 0.03 and -16.5 ± 1.21 mV, respectively. DOX-BAC-SNEDDs had a higher AUC0-t values of 6128.84 ± 68.71 and 5896.62 ± 99.31 ng/mL/h as compared with DOX-BAC suspension.Conclusion: These findings hold promise for advancing breast cancer treatment and facilitating therapeutic drug monitoring.

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Doxorubicin-Loaded Ultrasmall Gold Nanoparticles (1.5 nm) for Brain Tumor Therapy and Assessment of Their Biodistribution.

Ultrasmall gold nanoparticles (1.5 nm) were covalently conjugated with doxorubicin (AuDox) and AlexaFluor647 (AuAF647) to assess their biodistribution and their efficiency toward brain tumors (glioblastoma). A thorough characterization by transmission electron microscopy, small-angle X-ray scattering, and differential centrifugal sedimentation confirmed their uniform ultrasmall nature which makes them very mobile in the body. Each nanoparticle carried either 13 doxorubicin molecules (AuDox) or 2.7 AlexaFluor-647 molecules (AuAF647). The firm attachment of the ligands to the nanoparticles was demonstrated by their resilience to extensive washing, followed by centrifugation. The particles easily entered mammalian cells (HeLa, T98-G, brain endothelial cells, and human astrocytes) due to their small size. The intravenously delivered fluorescing AuAF647 nanoparticles crossed the blood-brain barrier with ∼23% accumulation in the brain tumor in an orthotopic U87 brain tumor model in nude mice. This was confirmed by elemental analysis (gold; inductively coupled plasma optical emission spectroscopy) in various organs. The doxorubicin-loaded AuDox nanoparticles inhibited brain tumor growth and prolonged animal survival without adverse side effects. Most of the nanoparticles (84%) had been excreted from the animal after 24 h, indicating a high mobility in the body.

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats.

All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease. The aim of this study was to comprehensively characterise a novel model of HF with cardiorenal syndrome, i.e. DOXO-induced HFrEF with nephrotic syndrome, in which DOXO was administered to Ren-2 transgenic rats (TGR) via five intravenous injections in a cumulative dose of 10 mg/kg of body weight (BW). Our analysis included survival, echocardiography, as well as histological examination of the heart and kidneys, blood pressure, but also a broad spectrum of biomarkers to evaluate cardiac remodelling, fibrosis, apoptosis, oxidative stress and more. We have shown that the new model adequately mimics the cardiac remodelling described as "eccentric chamber atrophy" and myocardial damage typical for DOXO-related cardiotoxicity, without major damage of the peritoneum, lungs and liver. This pattern corresponds well to a clinical situation of cancer patients receiving anthracyclines, where HF develops with some delay after the anticancer therapy. Therefore, this study may serve as a comprehensive reference for all types of research on DOXO-related cardiotoxicity, proving especially useful in the search for new therapeutic strategies.

Hybrid Liposome-MSN System with Co-Delivering Potential Effective Against Multidrug-Resistant Tumor Targets in Mice Model.

Introduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

Expression of cancer susceptibility candidate 11 in ovarian cancer tissues and its role in doxorubicin resistance.

We aimed to investigate the expression of cancer susceptibility candidate 11 (CASC11) in ovarian cancer (OC) tissues and its role in doxorubicin (Dox) resistance. A total of 98 patients were included as subjects. Reverse transcription-polymerase chain reaction was employed to determine the expressions of CASC11 in OC and para-OC tissues, and in OC cells (A2780, SKOV3, OVCAR3 and A547) and human normal ovarian epithelial cells (IOSE-80) from these patients. OC SKOV3/R cell line with Dox resistance was established and transfected with small interfering (si)-CASC11 to down-regulate CASC11 expression. Based on the constructed nude mouse model of orthotopic transplanted tumor, the growth curves were plotted, and the changes in tumor volume and apoptosis were observed by hematoxylin-eosin staining. OC tissues had a significantly higher mRNA expression of CASC11 than that of para-OC tissues (P < 0.05). A547, OVCAR3, A2780 and SKOV3 cells had significantly higher mRNA expressions of CASC11 than that of IOSE-80 cells (P < 0.05). The transplanted tumor was significantly smaller in volume in the si-CASC11 group than that in the si-normal control (NC) group from the 8th days after transplanted tumor inoculation (P < 0.05). The tumor growth inhibition rate significantly rose in the si-CASC11 group in comparison with that in the si-NC group (P < 0.05). CASC11 has high expression in OC tissues. Knockout of CASC11 weakens the proliferative, invasive and migratory potentials and enhances the apoptotic potential of Dox-resistant OC cells, thereby reversing their Dox resistance.

The protective effect of Ghrelin peptide on doxorubicin hydrochloride induced heart failure in rats.

BACKGROUND: To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. METHODS: 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. RESULTS: After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P < 0.05), and left ventricular ejection fraction (LVEF) was significantly increased (P < 0.05). Compared with HF group, the left ventricular systolic pressure (LVSP), maximum rate of increase in left ventricular pressure (+ dP/dtmax) and maximum rate of decrease in left ventricular pressure (- dP/dtmax) of Ghrelin group was remarkedly increased (P < 0.05), left ventricular diastolic pressure (LVDP) decreased (P < 0.05). In the Ghrelin group, the degree and extent of cardiomyocyte degeneration and necrosis were remarkedly reduced compared with the HF group. The levels of TNF-α and iNOS in Ghrelin group were notably lower than those in HF group (P < 0.05), the IL-10 level increased markedly (P < 0.05). CONCLUSION: Ghrelin may reduce Dox-induced myocardial injury and improve cardiac function in rats by regulating inflammation and oxidative stress.

Pera orange juice (Citrus sinensis L. Osbeck) alters lipid metabolism and attenuates oxidative stress in the heart and liver of rats treated with doxorubicin.

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug widely used to treat cancer, but its use is limited due to multisystemic toxicity. Lipid metabolism is also affected by doxorubicin. Orange juice can reduce dyslipidemia in other clinical situations and has already been shown to attenuate cardiotoxicity. Our aim is to evaluate the effects of Pera orange juice (Citrus sinensis L. Osbeck) on mitigating lipid metabolism imbalance, metabolic pathways, and DOX induced cytotoxic effects in the heart and liver. Methods: Twenty-four male Wistar rats were allocated into 3 groups: Control (C); DOX (D); and DOX plus Pera orange juice (DOJ). DOJ received orange juice for 4 weeks, while C and D received water. At the end of each week, D and DOJ groups received 4 mg/kg/week DOX, intraperitoneal. At the end of 4 weeks animals were submitted to echocardiography and euthanasia. Results: Animals treated with DOX decreased water intake and lost weight over time. At echocardiography, DOX treated rats presented morphologic alterations in the heart. DOX increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. It also reduced superoxide dismutase (SOD) activity, increased protein carbonylation in the heart and dihydroethidium (DHE) expression in the liver, decreased glucose transporter type 4 (GLUT4) and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ1) in the heart, and reduced carnitine palmitoyltransferase I (CPT1) in the liver. Conclusion: DOX caused dyslipidemia, liver and cardiac toxicity by increasing oxidative stress, and altered energy metabolic parameters in both organs. Despite not improving changes in left ventricular morphology, orange juice did attenuate oxidative stress and mitigate the metabolic effects of DOX.

In vivo cardioprotective effect of zinc oxide nanoparticles against doxorubicin-induced myocardial infarction by enhancing the antioxidant system and nitric oxide production.

BACKGROUND: Myocardial infarction (MI) is the result of reduced or stopped blood supply to a section of the myocardium. Regardless of its potential effectiveness in the treatment of several types of cancers, doxorubicin (DOX) capabilities are restricted because of its widespread cardiotoxic impact. AIM: In this study, the protective effect of zinc oxide nanoparticles against doxorubicin-induced myocardial infarction in rats is examined. METHODS: Zinc oxide nanoparticles (ZnO NPs) were synthesized and characterized using X-ray diffraction, transmission electron microscope, and UV-Vis spectral analysis. A total cumulative dose of DOX (18 mg/kg body weight, i.p.) was injected once daily on days 2, 4, 6, 8, 10, and 12 (i.p.) to induce MI in rats. 24 rats were divided into 4 groups; control, MI, and MI treated with two doses of ZnO NPs (45 and 22.5 mg/kg). RESULTS: The treatment with ZnO NPs restored ST-segment near normal, ameliorated the changes in cardiac troponin T, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, total proteins, malondialdehyde, nitric oxide, reduced glutathione, and catalase.The histological investigation revealed that ZnO NPs treated group showed marked improvement in the examined cardiac muscle and liver in numerous sections.The lower dose of ZnO NPs (22.5 mg/kg) was significantly more effective than the higher dose (45 mg/kg). CONCLUSION: The effect of ZnO NPs against doxorubicin-induced myocardial infarction in rats was assessed and the results revealed a successful cardioprotective potency through enhancing the antioxidant system and stimulating nitric oxide production in myocardial infarcted rats. This work implies that ZnO NPs could serve as promising agents for treating doxorubicin-induced cardiotoxicity.

Investigation of Dual-Loaded Doxorubicin and Sorafenib Liposomes Co-Modified with Glycyrrhetinic Acid and Cell-Penetrating Peptide TAT.

BACKGROUND: Combining Doxorubicin (DOX) with sorafenib (SF) is a promising strategy for treating Hepatocellular Carcinoma (HCC). However, strict dosage control is required for both drugs, and there is a lack of target selectivity. OBJECTIVE: This study aims to develop a novel nano-drug delivery system for the combined use of DOX and SF, aiming to reduce their respective dosages, enhance therapeutic efficacy, and improve target selectivity. METHODS: DOX/SF co-loaded liposomes (LPs) were prepared using the thin-film hydration method. The liposomes were modified with 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE)- polyethylene glycol (PEG2000), DSPE-PEG1000-cell penetrating peptide TAT, and Glycyrrhetinic Acid (GA). The basic properties of the liposomes were characterized. CCK-8 cell viability assays were conducted using HepG2, MHCC97-H, and PLC cell models, and apoptosis experiments were performed using HepG2 cells to determine if this delivery system could reduce the respective dosages of DOX and SF and enhance HCC cytotoxicity. Liposome uptake experiments were performed using HepG2 cells to validate the target selectivity of this delivery system. RESULTS: A GA/TAT-DOX/SF-LP liposomal nano drug delivery system was successfully constructed, with a particle size of 150 nm, a zeta potential of -7.9 mV, a DOX encapsulation efficiency of 92%, and an SF encapsulation efficiency of 88.7%. Cellular experiments demonstrated that this delivery system reduced the required dosages of DOX and SF, exhibited stronger cytotoxicity against liver cancer cells, and showed better target selectivity. CONCLUSION: A simple and referenceable liposomal nano drug delivery system has been developed for the combined application of DOX and SF in hepatocellular carcinoma treatment.

Modulatory effects of miRNAs in doxorubicin resistance: A mechanistic view.

MicroRNAs (miRNAs) are a group of small non-coding RNAs and play an important role in controlling vital biological processes, including cell cycle control, apoptosis, metabolism, and development and differentiation, which lead to various diseases such as neurological, metabolic disorders, and cancer. Chemotherapy consider as gold treatment approaches for cancer patients. However, chemotherapeutic is one of the main challenges in cancer management. Doxorubicin (DOX) is an anti-cancer drug that interferes with the growth and spread of cancer cells. DOX is used to treat various types of cancer, including breast, nervous tissue, bladder, stomach, ovary, thyroid, lung, bone, muscle, joint and soft tissue cancers. Also recently, miRNAs have been identified as master regulators of specific genes responsible for the mechanisms that initiate chemical resistance. miRNAs have a regulatory effect on chemotherapy resistance through the regulation of apoptosis process. Also, the effect of miRNAs p53 gene as a key tumor suppressor was confirmed via studies. miRNAs can affect main biological pathways include PI3K pathway. This review aimed to present the current understanding of the mechanisms and effects of miRNAs on apoptosis, p53 and PTEN/PI3K/Akt signaling pathway related to DOX resistance.

Astragaloside IV intervenes multi-regulatory cell death forms against doxorubicin-induced cardiotoxicity by regulating AMPKα2 pathway.

The clinical use of doxorubicin has been severely limited by doxorubicin-induced cardiotoxicity (DIC). Its mechanism is extremely complex and involves reactive oxygen species overgeneration, DNA damage, and aberrant inflammatory activity, which also involves multi-regulatory cell death mechanisms, including apoptosis, autophagy, and pyroptosis. These mechanisms overlap and crosstalk, resulting in the poor intervention of DIC injury. Astragaloside IV (Ast) has polybioactivity and mitigates DIC damage; however, the underlying mechanisms remain unknown. This study aimed to investigate whether Ast pretreatment (Ast-pre) could protect the myocardium against DIC damage and the underlying mechanisms. In particular, the relationship between Ast-pre, AMPKα2 activity, autophagy, apoptosis, and pyroptosis was explored. Firstly, DIC injury models were established using neonatal rat cardiomyocytes (NRCMs) and mice. And then the effects of adaptive autophagy, anti-pyroptosis and anti-apoptosis of Ast-pre were detected using multi-relevant indexes in NRCMs. Further, how does Ast-pre in AMPKα2 phosphorylation was explored. Finally, these results were validated by DIC injury in mice. Ast-pre, similar to disulfiram (pyroptosis inhibitor), effectively alleviated the inflammatory response, inhibited oxidative and energy stress, prevented mitochondrial dysfunction, and protected the myocardium resisting DIC damage, as demonstrated using multi-indexes. The protection of Ast-pre to DIC damage was almostly canceled by paclitaxel (pyroptosis inducer), 3-methyladenine (autophagy inhibitor), and pAD/AMPKα2-shRNA or compound C (AMPK inhibitor) to varying degrees. In conclusion, Ast-pre could upregulate and activate AMPKα2, enhance adaptive autophagy, and improve energy metabolism and mitochondrial function, thereby alleviate DIC-induced pyroptosis and apoptosis in NRCMs and mice.

Rhein Alleviates Doxorubicin-Induced Myocardial Injury by Inhibiting the p38 MAPK/HSP90/c-Jun/c-Fos Pathway-Mediated Apoptosis.

Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis.

In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis.

In addition to residual tumor cells, surgery-induced inflammation significantly contributes to tumor recurrence and metastasis by recruiting polymorphonuclear neutrophils (PMNs) and promoting their involvement in tumor cell proliferation, invasion and immune evasion. Efficiently eliminating residual tumor cells while concurrently intervening in PMN function represents a promising approach for enhanced postoperative cancer treatment. Here, a chitosan/polyethylene oxide electrospun fibrous scaffold co-delivering celecoxib (CEL) and doxorubicin-loaded tumor cell-derived microparticles (DOX-MPs) is developed for postoperative in-situ treatment in breast cancer. This implant (CEL/DOX-MPs@CP) ensures prolonged drug retention and sustained release within the surgical tumor cavity. The released DOX-MPs effectively eliminate residual tumor cells, while the released CEL inhibits the function of inflammatory PMNs, suppressing their promotion of residual tumor cell proliferation, migration and invasion, as well as remodeling the tumor immune microenvironment. Importantly, the strategy is closely associated with interference in neutrophil extracellular trap (NET) released from inflammatory PMNs, leading to a substantial reduction in postoperative tumor recurrence and metastasis. Our results demonstrate that CEL/DOX-MPs@CP holds great promise as an implant to enhance the prognosis of breast cancer patients following surgery.

Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Aerobic Exercise Attenuates Doxorubicin-Induced Cardiomyopathy by Suppressing NLRP3 Inflammasome Activation in a Rat Model.

Doxorubicin (DOX) is a potent chemotherapeutic agent with well-documented dose-dependent cardiotoxicity. Regular exercise is recognized for its cardioprotective effects against DOX-induced cardiac inflammation, although the precise mechanisms remain incompletely understood. The activation of inflammasomes has been implicated in the pathogenesis and treatment of DOX-induced cardiotoxicity, with the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome emerging as a key mediator in cardiovascular inflammation. This study aimed to investigate the role of exercise in modulating the NLRP3 inflammasome to protect against DOX-induced cardiac inflammation. Male Sprague-Dawley rats were randomly assigned to receive a 10-day course of DOX or saline injections, with or without a preceding 10-week treadmill running regimen. Cardiovascular function and histological changes were subsequently evaluated. DOX-induced cardiotoxicity was characterized by cardiac atrophy, systolic dysfunction, and hypotension, alongside activation of the NLRP3 inflammasome. Our findings revealed that regular exercise preserved cardiac mass and hypertrophic indices and prevented DOX-induced cardiac dysfunction, although it did not fully preserve blood pressure. These results underscore the significant cardioprotective effects of exercise against DOX-induced cardiotoxicity. While regular exercise did not entirely prevent DOX-induced hypotension, our findings demonstrate that it confers protection against DOX-induced cardiotoxicity by suppressing NLRP3 inflammasome activation in the heart, underscoring its anti-inflammatory role. Further research should explore the temporal dynamics and interactions among exercise, pyroptosis, and other pathways in DOX-induced cardiotoxicity to enhance translational applications in cardiovascular medicine.

Cytotoxicity of Doxorubicin-Curcumin Nanoparticles Conjugated with Two Different Peptides (CKR and EVQ) against FLT3 Protein in Leukemic Stem Cells.

A targeted micellar formation of doxorubicin (Dox) and curcumin (Cur) was evaluated to enhance the efficacy and reduce the toxicity of these drugs in KG1a leukemic stem cells (LSCs) compared to EoL-1 leukemic cells. Dox-Cur-micelle (DCM) was developed to improve the cell uptake of both compounds in LSCs. Cur-micelle (CM) was produced to compare with DCM. DCM and CM were conjugated with two FLT3 (FMS-like tyrosine kinase)-specific peptides (CKR; C and EVQ; E) to increase drug delivery to KG1a via the FLT3 receptor (AML marker). They were formulated using a film-hydration technique together with a pH-induced self-assembly method. The optimal drug-to-polymer weight ratios for the DCM and CM formulations were 1:40. The weight ratio of Dox and Cur in DCM was 1:9. DCM and CM exhibited a particle size of 20-25 nm with neutral charge and a high %EE. Each micelle exhibited colloidal stability and prolonged drug release. Poloxamer 407 (P407) was modified with terminal azides and conjugated to FLT3-targeting peptides with terminal alkynes. DCM and CM coupled with peptides C, E, and C + E exhibited a higher particle size. Moreover, DCM-C + E and CM-C + E showed the highest toxicity in KG-1a and EoL-1 cells. Using two peptides likely improves the probability of micelles binding to the FLT3 receptor and induces cytotoxicity in leukemic stem cells.

Engineering Novel Amphiphilic Platinum(IV) Complexes to Co-Deliver Cisplatin and Doxorubicin.

In this study, we report a novel platinum-doxorubicin conjugate that demonstrates superior therapeutic indices to cisplatin, doxorubicin, or their combination, which are commonly used in cancer treatment. This new molecular structure (1) was formed by conjugating an amphiphilic Pt(IV) prodrug of cisplatin with doxorubicin. Due to its amphiphilic nature, the Pt(IV)-doxorubicin conjugate effectively penetrates cell membranes, delivering both cisplatin and doxorubicin payloads intracellularly. The intracellular accumulation of these payloads was assessed using graphite furnace atomic absorption spectrometry and fluorescence imaging. Since the therapeutic effects of cisplatin and doxorubicin stem from their ability to target nuclear DNA, we hypothesized that the amphiphilic Pt(IV)-doxorubicin conjugate (1) would effectively induce nuclear DNA damage toward killing cancer cells. To test this hypothesis, we used flow the cytometric analysis of phosphorylated H2AX (γH2AX), a biomarker of nuclear DNA damage. The Pt(IV)-doxorubicin conjugate (1) markedly induced γH2AX in treated MDA-MB-231 breast cancer cells, showing higher levels than cells treated with either cisplatin or doxorubicin alone. Furthermore, MTT cell viability assays revealed that the enhanced DNA-damaging capability of complex 1 resulted in superior cytotoxicity and selectivity against human cancer cells compared to cisplatin, doxorubicin, or their combination. Overall, the development of this amphiphilic Pt(IV)-doxorubicin conjugate represents a new form of combination therapy with improved therapeutic efficacy.

Effect of AMH on primordial follicle populations in mouse ovaries and human pre-pubertal ovarian xenografts during doxorubicin treatment.

Introduction: Survival rates of the childhood cancer patients are improving, however cancer treatments such as chemotherapy may lead to infertility due to loss of the primordial follicle (PMF) reserve. Doxorubicin (DXR) is a gonadotoxic chemotherapy agent commonly used in childhood cancers. Anti-Müllerian Hormone (AMH) has been reported to have a protective effect on the mouse ovarian reserve against DXR in vivo. However, whether AMH can prevent PMF loss in conjunction with DXR in human ovarian tissue in vivo has not been determined. Methods: In order to investigate this, we first established an optimum dose of DXR that induced PMF loss in cultured mouse ovaries and investigated the efficacy of AMH on reducing DXR-induced PMF loss in mice in vitro. Second, we investigated the effects of DXR on pre-pubertal human ovarian tissue and the ability of AMH to prevent DXR-induced damage comparing using a mouse xenograft model with different transplantation sites. Results: Mouse ovaries treated with DXR in vitro and in vivo had reduced PMF populations and damaged follicle health. We did not observe effect of DXR-induced PMF loss or damage to follicle/stromal health in human ovarian cortex, this might have been due to an insufficient dose or duration of DXR. Although AMH does not prevent DXR-induced PMF loss in pre-pubertal and adult mouse ovaries, in mouse ovaries treated with higher concentration of AMH in vitro, DXR did not cause a significant loss in PMFs. This is the first study to illustrate an effect of AMH on DXR-induced PMF loss on pre-pubertal mouse ovaries. However, more experiments with higher doses of AMH and larger sample size are needed to confirm this finding. Discussion: We did not observe that AMH could prevent DXR-induced PMF loss in mouse ovaries in vivo. Further studies are warranted to investigate whether AMH has a protective effect against DXR in xenotransplanted human ovarian tissue. Thus, to obtain robust evidence about the potential of AMH in fertility preservation during chemotherapy treatment, alternative AMH administration strategies need to be explored alongside DXR administration to fully interrogate the effect of DXR and AMH on human xenografted tissues.