-
Proceedings of the National Academy of... Jun 2020The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly...
The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
Topics: Animals; Antineoplastic Agents; Cell Line; Chromatin; DNA Damage; Doxorubicin; Heart Diseases; Histones; Humans; Leukemia, Myeloid, Acute; Mice
PubMed: 32554494
DOI: 10.1073/pnas.1922072117 -
Biochimie Sep 2022
Topics: Melatonin; Doxorubicin; Antineoplastic Agents; Apoptosis
PubMed: 35569703
DOI: 10.1016/j.biochi.2022.05.005 -
Scientific Reports Oct 2020The widespread clinical use of the cytostatic doxorubicin together with the induction of chronic cardiomyopathy necessitates the conduct of further pharmacokinetic...
The widespread clinical use of the cytostatic doxorubicin together with the induction of chronic cardiomyopathy necessitates the conduct of further pharmacokinetic trials. Novel analytical technologies suitable for point-of-care applications can facilitate drug level analyses but might be prone to interferences from structurally similar compounds. Besides the alcohol metabolite doxorubicinol, aglycone metabolites of doxorubicin might affect its determination in plasma. To evaluate their analytical relevance, a validated HPLC method for the quantification of doxorubicin, doxorubicinol and four aglycones was used. The degradation pattern of doxorubicin in plasma under long-term storage was analysed with respect to the formation of aglycone products. In addition, overall 50 clinical samples obtained within the EPOC-MS-001-Doxo trial were analysed. Substantial degradation of doxorubicin in plasma occurred within a storage period of one year, but this did not lead to the formation of aglycones. In clinical samples, 7-deoxydoxorubicinolone was the major aglycone detectable in 35/50 samples and a concentration range of 1.0-12.7 µg L. If at all, the other aglycones were only determined in very low concentrations. Therefore, analytical interferences from aglycones seem to be unlikely with the exception of 7-deoxydoxorubicinolone whose concentration accounted for up to 65% of the doxorubicin concentration in the clinical samples analysed.
Topics: Chromatography, High Pressure Liquid; Doxorubicin; Drug Monitoring; Humans; Plasma
PubMed: 33122763
DOI: 10.1038/s41598-020-75662-w -
Investigational New Drugs 1983The pharmacokinetics of 4'-epi-doxorubicin (4'-epi-adriamycin, 4'-epi-DX) in man can be described by a three-compartment model with a rapid distribution phase and a very... (Comparative Study)
Comparative Study
The pharmacokinetics of 4'-epi-doxorubicin (4'-epi-adriamycin, 4'-epi-DX) in man can be described by a three-compartment model with a rapid distribution phase and a very long elimination phase. Urine excretion amounts to a total of about 11% of the administered dose during 48 h after drug administration, and less than 1% during the following 48 h. In plasma 4'-epi-doxorubicin is rapidly converted to five metabolites (4'-epi-doxorubicinol, aglycones and glucuronides), the concentration of the aglycones sometimes exceeding that of 4'-epi-DX. In urine only three metabolites were found in addition to the parent drug; they were identified as 4'-epi-doxorubicinol (EOH), 4'-epi-doxorubicin-glucuronide (E-Glu) and 4'-epi-doxorubicinol-glucuronide (EOH-Glu). Comparison of the pharmacokinetics and metabolic profiles of 4'-epi-DX and doxorubicin (DX) in man revealed that 4'-epi-DX eliminates faster than DX.
Topics: Chromatography, High Pressure Liquid; Doxorubicin; Epirubicin; Humans; Kinetics; Structure-Activity Relationship
PubMed: 6590528
DOI: 10.1007/BF00180192 -
Journal of Controlled Release :... Jul 2002Doxorubicin was chemically conjugated to the terminal end of a di-block copolymer composed of poly(L-lactic acid) (PLLA) and methoxy-poly(ethylene glycol) (mPEG) via two...
Doxorubicin was chemically conjugated to the terminal end of a di-block copolymer composed of poly(L-lactic acid) (PLLA) and methoxy-poly(ethylene glycol) (mPEG) via two acid-cleavable linkages. A hydrazone bond and a cis-acotinyl bond were formed between doxorubicin and the terminal group of PLLA segment in the block copolymer. Doxorubicin-conjugated PLLA-mPEG di-block copolymers self-assembled to form micelles in aqueous solution. The doxorubicin-conjugated micelles were about 89.1 nm in diameter and their critical micelle concentration was 1.3 microg/ml. These values were comparable with those of unconjugated micelles. In an acidic condition, the conjugated doxorubicin in the hydrazone linkage was readily cleaved, releasing doxorubicin in an intact structure. Doxorubicin-conjugated PLLA-mPEG micelles were more potent in cell cytotoxicity than free doxorubicin, suggesting that they were more easily taken up within cells with concomitant rapid release of cleaved doxorubicin into the cytoplasm from acidic endosomes.
Topics: Biocompatible Materials; Cell Survival; Doxorubicin; Drug Delivery Systems; Humans; Micelles; Polyesters; Polymers; Tumor Cells, Cultured
PubMed: 12106973
DOI: 10.1016/s0168-3659(02)00088-3 -
International Journal of Biological... Nov 2022The present study synthesized a new kind of pH-responsive active targeting glycodendrimer (ATGD) for doxorubicin delivery to cancerous cells. First, the glycodendrimer...
The present study synthesized a new kind of pH-responsive active targeting glycodendrimer (ATGD) for doxorubicin delivery to cancerous cells. First, the glycodendrimer was synthesized based on the cultivation of chitosan dendrons on amine-functionalized, silica-grafted cellulose nanocrystals. Afterward, glycodendrimer was conjugated with folic acid to provide a folate receptor-targeting agent. The response surface method was employed to obtain the optimum conditions for the preparation of doxorubicin-loaded ATGD. The effect of doxorubicin/ATGD ratio, temperature, and pH on doxorubicin loading capacity was evaluated, and high loading capacity was achieved under optimized conditions. After determining doxorubicin release pattern at acidic and physiological pH, ATGD cytotoxicity was surveyed by MTT assay. Based on the results, the loading behavior of doxorubicin onto ATGD was in good agreement with monolayer-physisorption, and drug release was Fickian diffusion-controlled. ATGD could release the doxorubicin much more at acidic pH than physiological pH, corresponding to pH-responsive release behavior. Results of MTT assay confirmed the cytotoxicity of doxorubicin-loaded ATGD in cancer cells, while ATGD (without drug) was biocompatible with no tangible toxicity. These results suggested that ATGD has the potential for the treatment of cancer.
Topics: Hydrogen-Ion Concentration; Doxorubicin; Drug Liberation; Chitosan; Nanoparticles; Drug Delivery Systems; Drug Carriers
PubMed: 36089082
DOI: 10.1016/j.ijbiomac.2022.09.037 -
Tissue & Cell Dec 2023Luminal-B type human breast cancer cell line (BT-474) to assess the synergistic effects of ozone applied after chemotherapeutic treatment with various dosages of...
OBJECTIVE
Luminal-B type human breast cancer cell line (BT-474) to assess the synergistic effects of ozone applied after chemotherapeutic treatment with various dosages of doxorubicin, and compare the results with the effects on L929 fibroblast cell line.
METHODS
Doxorubicin (1-50 M) was added to each cell lines and left to sit for 24 h at 37 °C. Then, as combination groups, half of the groups were incubated with 30 g/mL ozone for 25 min. Tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and matrix metalloproteinase-2 and - 9 (MMP-2 and MMP-9) levels were measured using the MTT test, flow cytometry, and immunocytochemistry, respectively.
RESULTS
When compared to simply doxorubicin-applied cells without ozone treatment, each dose of doxorubicin + ozone treatment considerably boosted L929 viability but significantly decreased BT-474 viability. Additionally, the combination increased the apoptotic impact of doxorubicin on BT-474 but not L929 (P < 0.001). TGF-, MMP-2, and MMP-9 levels of L929 after combination were substantially higher than those of the other groups (P < 0.01). Doxorubicin's effect on BT-474's protein levels, which had significantly decreased in comparison to those of the other groups, was reversed by the combination treatment (P < 0.05).
CONCLUSION
Doxorubicin's anti-proliferative and apoptotic effects were enhanced by ozone treatment in BT-474 cells, but it also repaired and healed healthy fibroblast cells that had been harmed by the cytotoxicity of the chemotherapy drug. If doxorubicin and ozone treatment are coupled, BT-474 cells may develop resistance to it through expressions of TNF-α, TGF-β, MMP-2, and MMP-9.
Topics: Humans; Female; Breast Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Tumor Necrosis Factor-alpha; Doxorubicin; Cell Line; Apoptosis; Transforming Growth Factor beta; Cell Proliferation; Cell Line, Tumor
PubMed: 37866151
DOI: 10.1016/j.tice.2023.102233 -
Annales Pharmaceutiques Francaises Jun 2023The present study aimed to evaluate the effect of metformin pretreatment on the potentiation of antiproliferative action of doxorubicin against breast cancer.
OBJECTIVES
The present study aimed to evaluate the effect of metformin pretreatment on the potentiation of antiproliferative action of doxorubicin against breast cancer.
MATERIAL AND METHODS
Female Wistar rats were administered with 7,12-Dimethylbenz(a)anthracene (DMBA) (35mg) in 1mL olive oil subcutaneously beneath the mammary gland. Animals were pretreated with metformin (Met) 200mg/kg two weeks before DMBA administration. DMBA control groups received doxorubicin (Dox) (4mg/kg and 2mg/kg), Met (200mg/kg) alone and in combination with Dox (4mg/kg). Met pre-treated DMBA control groups received Dox 4mg/kg and 2mg/kg.
RESULTS
Met pre-treated groups treated with Dox exhibited a decrease in tumor incidence, tumor volume and increased survival rate than the DMBA group. Organ-to-body weight ratios and histopathology of heart, liver and lungs of Met pre-treated groups treated with Dox showed lesser toxicity than Dox treated DMBA control groups. There was a noteworthy decrease in malondialdehyde levels and a substantial increase in the levels of reduced glutathione together with a significant decrease in the levels of inflammatory markers like IL-6, IL-1β and NF-κB in Met pre-treated groups treated with Dox. Histopathology of breast tumors revealed better control of tumors in Met pre-treated groups treated with Dox than DMBA control group. Immunohistochemistry and real-time PCR data revealed a significant reduction in Ki67 expression in Met pre-treated groups treated with Dox as compared to the DMBA control group.
CONCLUSION
The present study suggests that metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer.
Topics: Rats; Animals; Female; 9,10-Dimethyl-1,2-benzanthracene; Metformin; Rats, Wistar; Doxorubicin; Neoplasms
PubMed: 36907329
DOI: 10.1016/j.pharma.2023.03.001 -
International Journal of Molecular... Apr 2023Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds....
Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds. Here, hyaluronic acid (HA) was esterified with benzyl groups to prepare hyaluronic acid derivative (HA-Bn) nanofibers via electrospinning. Electrospun membranes with average fiber diameters of 407.64 ± 124.8 nm (H400), 642.3 ± 228.76 nm (H600), and 841.09 ± 236.86 nm (H800) were obtained by adjusting the spinning parameters. These fibrous membranes had good biocompatibility, among which the H400 group could promote the proliferation and spread of L929 cells. Using the postoperative treatment of malignant skin melanoma as an example, the anticancer drug doxorubicin (DOX) was encapsulated in nanofibers via hybrid electrospinning. The UV spectroscopy of DOX-loaded nanofibers (HA-DOX) revealed that DOX was successfully encapsulated, and there was a π-π interaction between aromatic DOX and HA-Bn. The drug release profile confirmed the sustained release of about 90%, achieved within 7 days. In vitro cell experiments proved that the HA-DOX nanofiber had a considerable inhibitory effect on B16F10 cells. Therefore, the HA-Bn electrospun membrane could facilitate the potential regeneration of injured skin tissues and be incorporated with drugs to achieve therapeutic effects, offering a powerful approach to developing therapeutic and regenerative biomaterial.
Topics: Biocompatible Materials; Hyaluronic Acid; Nanofibers; Doxorubicin; Antineoplastic Agents
PubMed: 37108186
DOI: 10.3390/ijms24087023 -
Histology and Histopathology Oct 2004This study was designed to investigate the preventive effect of melatonin on doxorubicin's most important side effect, cardiotoxicity. Forty male albino Wistar rats were...
This study was designed to investigate the preventive effect of melatonin on doxorubicin's most important side effect, cardiotoxicity. Forty male albino Wistar rats were utilized and the rats were divided into five groups: group I, 0.9% NaCl for 4 days; group II, doxorubicin 3 mg/kg/day for 4 days; group III, 2.5 % ethanol for 15 days; group IV, melatonin 6 mg/kg/day for 15 days; and group V, a doxorubicin and melatonin combination were administered intraperitoneally. At the end of the experiment, tissue samples obtained from the cardiac muscle of the left ventricle of the rats were processed for measurement of malondialdehyde and for electron microscopic examination. Malondialdehyde, a product of lipid peroxidation, was found to be significantly higher in the doxorubicin group. However, in the doxorubicin and melatonin combination group the level of malondialdehyde was decreased statistical significant. The histological examination revealed destruction of myofibrils, disorganization of sarcomeres, mitochondrial degeneration and formation of giant mitochondria and lipid accumulation in the doxorubicin group. Also, accumulation of filamentous structures in the sarcoplasma in some of the cells, structural changes in capillaries and an increase in collagen fibers forming bundles were observed. When melatonin was added to the doxorubicin treatment all structural changes were reduced. The cardiotoxic side effect of doxorubicin used as a chemotherapeutic agent and was probably developed as a result of suppression of the antioxidant system and lipid peroxidation. Therefore, it could be assumed that the addition of melatonin in the treatment of doxorubicin could prevent the cardiotoxicity of doxorubicin.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Heart; Lipid Peroxidation; Male; Malondialdehyde; Melatonin; Microscopy, Electron; Mitochondria, Heart; Myocardium; Rats; Rats, Wistar
PubMed: 15375752
DOI: 10.14670/HH-19.1101