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Results for “Doxorubicin”

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At least 19 recordsLinked to original sources

PubMed1979

Elevation of serum lipid peroxide level associated with doxorubicin toxicity and its amelioration by [dl]-alpha-tocopheryl acetate or coenzyme Q10 in mouse (doxorubicin, toxicity, lipid peroxide, tocopherol, coenzyme Q10).

Elevations of serum lipid peroxide levels were demonstrated in mice after an equitoxic dose of doxorubicin. When BDF1 mice were injected with doxorubicin (20 mg/kg body weight, IP), lipid peroxide levels in sera were elevated 1 day after the injection and the levels declined on subsequent days. 5-Fluorouracil (400 mg/kg body weight, IP) never changed the peroxide levels in serum. Furthermore, it was found that the co-administration of [dl]-alpha-tocopheryl acetate or coenzyme Q10 IM strongly inhibited the doxorubicin-induced elevation of lipid peroxides in serum. The effectiveness of [dl]-alpha-tocopheryl acetate or coenzyme Q10 in reducing the lethality of doxorubicin in mice was also confirmed. These results indicate that the measurement of serum 2-thiobarbituric acid-reacting substances provided a useful measurement of lipid peroxide levels, which may be involved in some way with doxorubicin toxicity, and that the administration of antioxidants provide protection against some of the side effects of doxorubicin.

Animals↗

PubMed1979

Inhibition of drug oxidation and stimulation of NADPH oxidase in vitro by doxorubicin and triferric-doxorubicin.

The electrophilic properties of the quinone-hydroquinone configuration of anthracycline antibiotics suggests a possible influence on cytochrome P-450-mediated mono-oxygenase reactions. Both doxorubicin and triferric-doxorubicin (a derivative in which the quinone groups are blocked with iron) showed a similar dose-dependent inhibition of liver microsomal drug metabolism. A doxorubicin concentration-related stimulation of NADPH oxidase activity was found to be linear but that for triferric-doxorubicin was asymptotic. Neither inhibitor affected the activity of cytochrome c reductase, cytochrome b5 reductase or cytochrome P-450 reductase. However, doxorubicin did potentiate the inhibitory effect of aniline on cytochrome P-450 reductase and on ethylmorphine metabolism. It is concluded that these anthracyclines inhibit drug metabolism in vitro not by their electron-withdrawing potential but in a manner more similar to that described for type II compounds.

Aminophenols↗

PubMed2026

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

DNA methylation↗

PubMed1979

Risk factors for doxorubicin-induced congestive heart failure.

Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.

Adolescent↗

PubMed1979

Comparative study in mice of the toxicity, pharmacology, and therapeutic activity of daunorubicin-DNA and doxorubicin-DNA complexes.

We have compared the toxicologic, pharmacologic, and therapeutic properties of the DNA complexes of daunorubicin and doxorubicin, after intravenous (IV) administration into mice. The overall toxicity of doxorubicin is significantly reduced after IV injection as a DNA complex while daunorubicin-DNA is as toxic as free daunorubicin. On hemopoietic stem cells, daunorubicin-DNA was found to be more cytotoxic than daunorubicin, while the opposite was observed with doxorubicin and doxorubicin-DNA. Both complexes are more effective than the corresponding free drugs on the L1210 murine leukemia, when given IV at equitoxic doses. The tissue uptake in mice, after IV administration, is generally lower when the drugs are given bound to DNA. The stability of the two DNA complexes is very different in the bloodstream: daunorubicin-DNA behaves more like a prodrug of daunorubicin, while doxorubicin-DNA, remaining stable in the bloodstream, meets much more the requirements of an ideal drug-macromoleculare carrier entity.

Animals↗

PubMed2026

Potential contribution of the microbiota-gut-brain axis to doxorubicin-associated cognitive impairment: Mechanisms, evidence, and therapeutic opportunities.

Chemotherapy-induced cognitive impairment (CICI), often termed chemobrain, is a clinically important complication of cancer treatment that can affect memory, attention, executive function, and processing speed during and after therapy. Doxorubicin is of particular mechanistic interest because brain parenchymal exposure is limited, yet preclinical studies consistently identify neuroinflammatory, oxidative, vascular, and synaptic abnormalities after treatment. This critical narrative review evaluates whether intestinal injury and disruption of the microbiota-gut-brain axis may contribute to these central effects. Preclinical evidence indicates that doxorubicin can alter microbial community structure, injure the intestinal barrier, modify SCFA-associated taxa or predicted functions, alter selected metabolite profiles, and promote systemic inflammatory and metabolic signaling. These peripheral changes could interact with brain endothelial cells, glia, mitochondria, hippocampal neurogenesis, and synaptic-plasticity pathways. However, the proposed doxorubicin-gut-brain pathway remains a predominantly preclinical and incompletely tested framework. No longitudinal human study has yet established, within the same patients, the temporal sequence linking doxorubicin exposure, microbiome or metabolome changes, systemic inflammation, and objective cognitive outcomes. Existing animal studies also vary in dose, regimen, tumor context, sampling time, microbiome methodology, and control of behavioral or microbiological confounders, while causal rescue experiments remain limited. Key priorities are therefore longitudinal human cohorts with pretreatment baselines and repeated multi-omics and cognitive assessments; animal studies that test temporal precedence and causal rescue or pathway blockade in the same model; mediation analyses that determine whether microbial or metabolic changes lie between treatment and cognitive dysfunction; and mechanism-informed clinical trials that demonstrate target engagement, cognitive benefit, oncology safety, and preservation of antitumor efficacy. Microbiome-directed interventions are promising but remain investigational for doxorubicin-associated CICI.

blood–brain barrier↗

PubMed1979

DNA-binding parameters of daunorubicin and doxorubicin in the conditions used for studying the interaction of anthracycline-DNA complexes with cells in vitro.

Affinity constants of daunorubicin and doxorubicin for DNA at 37 degrees C and in presence of 10% serum were determined by an optical method and calculated from Scatchard plots. Values from 0.10 to 0.12 and from 0.13 to 0.16 X 10(6) M-1 were obtained for daunorubicin and doxorubicin, respectively. According to these affinity constants, the amounts of free drugs were calculated for various concentrations of daunorubicin-DNA or doxorubicin-DNA and for various molar ratios. In a large range of concentrations there is rather stable concentration of both free drugs, and these concentrations are inversely proportional to the nucleotides/drug ratio. The amount of free drug present in the medium is low as long as the concentration of daunorubicin-DNA or doxorubicin-DNA is higher than 1 microgram/ml (expressed as drug concentration). At lower concentrations, however, the percentage of free drug increases very sharply.

Cells, Cultured↗

PubMed2026

Bioinformatic analysis reveals the potential association of ESRP1 with the splicing of cytoskeleton-associated genes in doxorubicin-resistant MCF7 breast cancer cells.

BACKGROUND: Breast cancer remains one of the most prevalent malignancies among women, with doxorubicin resistance posing a significant challenge that undermines treatment success and survival outcomes. Aberrant alternative splicing (AS), driven by dysregulation or mutations in splicing factors (SFs), is implicated in cancer initiation, progression, and drug resistance. This study aims to investigate the association of the epithelial cell-specific splicing factor ESRP1 with doxorubicin resistance in breast cancer, focusing on how ESRP1 deficiency correlates with AS changes that promote chemoresistance. METHODS: We analyzed RNA-sequencing (RNA-seq) data from doxorubicin-resistant (MCF7-DR) and parental (MCF7) breast cancer cell lines to identify enhanced alternative splicing events (ASEs) and changes in ESRP1 expression; we further leveraged The Cancer Genome Atlas (TCGA)-BRCA cohort to construct an SF-RASE correlation network for screening core SFs (including ESRP1). An integrative analysis combining crosslinking immunoprecipitation (CLIP-seq) data and The Cancer Genome Atlas (TCGA) database was performed to validate ESRP1 binding targets and assess the association between ESRP1-related splicing and cytoskeleton organization. RESULTS: We observed extensive AS changes and significantly downregulated ESRP1 expression in MCF7-DR cells. Integrative analysis identified 61 high-confidence ASEs that correlate with ESRP1 expression. Further bioinformatic integration suggests that ESRP1 expression is associated with the splicing patterns of SPTBN1, MAP2K7, FGFR3, and CYB561A3-four genes involved in cytoskeleton organization-though direct experimental verification to confirm a causal regulatory relationship between ESRP1 and the splicing of these genes is still pending. CONCLUSIONS: Our findings suggest that ESRP1 expression is closely associated with doxorubicin resistance in breast cancer cells, with concomitant alterations in key ASEs linked to cytoskeletal remodeling that correlate with ESRP1. Exploring the ESRP1-related splicing network may offer new strategies to overcome chemoresistance and improve patient outcomes. However, the small cell line sample size (n = 2 per group) constrains the robustness of ASE and SF-ASE correlation findings, and these results should be interpreted with caution and require further validation with larger sample cohorts.

Alternative splicing↗

PubMed1979

Hyperthermia potentiates doxorubicin-related cardiotoxic effects.

The intercurrent administration of doxorubicin hydrochloride to a patient undergoing whole-body hyperthermia for the treatment of metastatic cancer repeatedly produced ventricular irritability and cardiac dysfunction. Individually, doxorubicin and hyperthermia were tolerated by the patient without incident. Catecholamine determinations showed that the administration of doxorubicin under hyperthermic conditions increased the liberation of both epinephrine and norepinephrine. The acute synergistic cardiotoxic effects occurred with doxorubicin dosages that were severalfold less than those associated with only mild and transient ECG disturbances under normothermic conditions.

Arrhythmias, Cardiac↗

PubMed1979

Study of the combined and separate administration of doxorubicin and coenzyme Q10 on mouse cardiac enzymes.

Administration of an acutely toxic dose of doxorubicin to mice did not increase, but rather decreased the percent deficiency of coenzyme Q10 (CoQ10) as calculated according to the coenzyme-apoenzyme system principle. The date indicate that doxorubicin may occupy CoQ10-empty receptors on the apoenzyme, with or without some destruction of enzyme-menbrane structure close to the receptor. Data from mice receiving both CoQ10 and doxorubicin indicated that CoQ10 may protect against doxorubicin. CoQ10 alone corrected the pre-existing deficiency found in control mice.

Animals↗

PubMed1979

Sudden death during doxorubicin administration.

Three patients are described who either died suddenly or had severe, life-threatening arrhythmias during or immediately after doxorubicin administration. Since doxorubicin and daunorubicin administration is known to be associated with acute EKG abnormalities, the acute decompensation in these patients appeared to be caused by the administration of these agents. The importance of careful observation of patients receiving doxorubicin, because of the possibility of acute cardiac arrhythmias, is stressed.

Arrhythmias, Cardiac↗

PubMed1977

In vitro adsorption of doxorubicin hydrochloride on insoluble calcium phosphate.

The adsorption of doxorubicin hydrochloride, a potent antitumor agent, on solid tribasic calcium phosphate was studied in vitro. A Langmuir adsorption isotherm at pH 7.4 and the maximum adsorption capacity of tribasic calcium phosphate were established. Tribasic calcium phosphate was chosen as a model for solid bone samples, which are stained with doxorubicin in patients who have received long-term doxorubicin therapy.

Adsorption↗

PubMed1979

Determination of daunorubicin, doxorubicin and their fluorescent metabolites by high-pressure liquid chromatography: plasma levels in DBA2 mice.

A rapid and nondestructive analytic method has been developed to separate and quantitate daunorubicin, doxorubicin, and their metabolites in biological fluids. This method combines the efficiency of high-pressure liquid chromatography and the sensitivity of fluorescence monitoring. The drug plasma levels achieved after IV administration of either daunorubicin or doxorubicin at 7 mg/kg into DBA2 mice were studied. The plasma disappearance curves are biphasic with a half-life of 1 min for the first elimination phase. In urine extracts, 13-hydroxy derivatives represent 80% of the fluorescence after injection of daunorubicin and only 4% after administration of doxorubicin.

Animals↗

PubMed1979

Ultrastructure of doxorubicin (adriamycin)-induced skin ulcers in rats.

Skin necrosis was produced in 24 male Fischer 344 rats by intradermal injection of 0.5 ml of doxorubicin (Adriamycin) at a concentration of 2 mg/ml. The resulting wounds healed slowly over 6 to 7 weeks with the reduced contraction rate paralleling the prolonged morbidity of doxorubicin ulcers in humans. Electron microscopy showed bizarre rough endoplasmic reticulum, double-walled vacuoles, and swollen mitochondria from 1 through 12 weeks after injury. Myofibroblasts with 60- to 80-A microfilaments with electron-dense bodies, intercellular connections, and prominent microtubules were seen from 4 through 12 weeks after injury. Although the appearance of myofibroblasts was delayed, their structure was normal. The delayed contraction of doxorubicin-induced skin ulcers thus appears due to persistent nonspecific cellular damage at the nuclear level rather than to specific derangement of myofibroblast function.

Animals↗

PubMed1979

Stability of refrigerated and frozen solutions of doxorubicin hydrochloride.

The stability of refrigerated and frozen solutions of doxorubicin hydrochloride was studied. Vials of doxorubicin hydrochloride with lactose (Adriamycin) were reconstituted with Sterile Water for Injection, USP, to provide a drug concentration of 2 mg/ml. Samples were refrigerated (4 C) for up to one year and frozen (-20C) for 30 days then assayed by high-performance liquid chromatography. One sample was assayed then refrozen each test period. Refrigerated and frozen samples showed no substantial loss of potency after six months and one month of storage, respectively. Filtration through a 0.22-micron filter did not affect potency. Degradation products were not detected, except for an unidentified small peak detected in the sample refrigerated for one year. Doxorubicin hydrochloride, when reconstituted with sterile water for injection, may be refrigerated for six months or frozen for one month without loss of potency.

Doxorubicin↗

PubMed1979

Uptake of free and DNA-bound daunorubicin and doxorubicin into human leukemic cells.

Leukemic cells from seven patients with acute nonlymphoblastic leukemia and granulocytes, and mononuclear cells from three healthy controls were isolated by centrifugation on metrozoate-dextran. The intracellular accumulation of both the free and DNA-bound forms of daunorubicin and doxorubicin was studied in vitro. The uptake of unbound daunorubicin was higher than that of doxorubicin. At drug concentrations of 1.75 microM and higher the uptake of the free drugs was greater than that of the bound forms, but at lower drug concentrations the uptake was about the same. This could at least partly be explained by a greater dissociation of the DNA-drug complexes at lower drug concentrations. The uptake into normal leukocytes was of the same order of magnitude as that into leukemic cells. There was a great interindividual variation in the accumulation of both free and DNA-bound drugs in the cells from leukemic patients. This variation might be of importance for the prediction of individual sensitivity to the different drugs.

Bone Marrow Cells↗

PubMed1978

Induction of remission in hepatocellular carcinoma with doxorubicin.

Doxorubicin (60 mg/m2 at 3-weekly intervals to a maximum total of 550 mg/m2) induced clinical remission in 14 (32%) of 44 patients with hepatocellular carcinoma. In 3 of those who responded, hepatic arteriography showed clearing of the previously extensive tumour circulation, and in a 4th there was disappearance of the tumour on serial ultrasound examinations. A fall in serum-alpha-fetoprotein level after the initial injection of doxorubicin predicted a favourable clinical response, whereas the level continued to rise in patients who did not respond.

Adult↗

PubMed2026

HDAC inhibition via suberoylanilide hydroxamic acid ameliorates doxorubicin-induced cardiotoxicity.

Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.

Doxorubicin↗