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International Journal of Molecular... Feb 2022Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially... (Review)
Review
Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades of research, treatment options remain limited. The mitochondria is commonly considered to be the main target of doxorubicin and mitochondrial dysfunction is the hallmark of doxorubicin-induced cardiotoxicity. Here, we review the pathogenic mechanisms of doxorubicin-induced cardiotoxicity and present an update on cardioprotective strategies for this disorder. Specifically, we focus on strategies that can protect the mitochondria and cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, and mitochondrial transfer. We also discuss the shortcomings of existing models of doxorubicin-induced cardiotoxicity and explore advances in the use of human pluripotent stem cell derived cardiomyocytes as a platform to facilitate the identification of novel treatments against this disorder.
Topics: Animals; Cardiotoxicity; Doxorubicin; Humans; Mitochondria, Heart; Neoplasms; Pluripotent Stem Cells
PubMed: 35163838
DOI: 10.3390/ijms23031912 -
Journal of Cancer Research and... 2014The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical... (Review)
Review
The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical approval against malignancies including solid tumours, transplantable leukemias and lymphomas was Doxorubicin HCl. This review is aimed at providing an overview of doxorubicin in cancer therapy. Pegylated liposomal doxorubicin has a polyethylene glycol (PEG) layer around doxorubicin-containing liposome as the result of a process known as pegylation. Non-pegylated liposomal doxorubicin (NPLD) was developed to overcome the drawbacks associated with previous formulations. Nudoxa; (NPLD) with its unique drug delivery system offers the benefit of pegylated liposomal doxorubicin without hand foot syndrome as the major side effect. Future studies will be directed towards estimating the costs of treatment with the novel liposomal doxorubicin formulations in order to assess their widespread use and robustness in treating patients with cancer.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Humans; Neoplasms; Polyethylene Glycols
PubMed: 25579518
DOI: 10.4103/0973-1482.139267 -
Bioorganic & Medicinal Chemistry Letters Oct 2013Doxorubicin-antioxidant multitarget compounds 6 and 7 were obtained by combining doxorubicin (DOX) with caffeic and ferulic acids through an ester linkage at C-14. The...
Doxorubicin-antioxidant multitarget compounds 6 and 7 were obtained by combining doxorubicin (DOX) with caffeic and ferulic acids through an ester linkage at C-14. The products were studied in in vitro models of cardiomyocytes and breast cancer cells, characterized by different degrees of resistance to DOX, due to different expressions of ATP binding cassette (ABC) transporters. Compound 7 was found to be less toxic than DOX in cardiomyocytes and to display the same possibly higher toxicity against the resistant breast cancer cells. This result shows that appropriate DOX-antioxidant co-drugs can limit the onset of cardiac damage, a significant side-effect of DOX, without impairing the antitumor activity of the parent antibiotic.
Topics: Animals; Antioxidants; Cell Line; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Resistance, Multiple; Female; Gene Expression Regulation; Humans; Molecular Structure; Myocytes, Cardiac
PubMed: 23973213
DOI: 10.1016/j.bmcl.2013.07.070 -
Molecules (Basel, Switzerland) Jul 2022The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases... (Review)
Review
The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.
Topics: Antineoplastic Agents; DNA Damage; Doxorubicin; Histones; Humans
PubMed: 35889350
DOI: 10.3390/molecules27144478 -
The Western Journal of Medicine Sep 1983Despite its vast utility in clinical oncology, the use of doxorubicin hydrochloride (Adriamycin) is limited by a potentially fatal cardiomyopathy. The following critical... (Review)
Review
Despite its vast utility in clinical oncology, the use of doxorubicin hydrochloride (Adriamycin) is limited by a potentially fatal cardiomyopathy. The following critical review, which examines the natural course, histopathologic effects, risk factors and monitoring indicators of this toxicity, also analyzes recent research of proposed mechanisms, including free radical formation with depletion of detoxifying enzymes, inhibition of vital enzyme systems and alterations in relative calcium concentrations. Prevention of the adverse reaction has been attempted by using such agents as alpha-tocopherol, selenium sulfide, coenzyme Q(10), sulfhydryl donors, nucleosides and razoxane, and via liposomal carriage and alternative methods of administration.
Topics: Biopsy; Cardiomyopathies; Dose-Response Relationship, Drug; Doxorubicin; Endocardium; Heart Function Tests; Humans; Myocardium; Risk
PubMed: 6356608
DOI: No ID Found -
Chembiochem : a European Journal of... Jan 2017Molecules that undergo activation or modulation following the addition of benign external small-molecule chemical stimuli have numerous applications. Here, we report the...
Molecules that undergo activation or modulation following the addition of benign external small-molecule chemical stimuli have numerous applications. Here, we report the highly efficient "decaging" of a variety of moieties by activation of a "self-immolative" linker, by application of water-soluble and stable tetrazine, including the controlled delivery of doxorubicin in a cellular context.
Topics: Apoptosis; Cell Line, Tumor; Cycloaddition Reaction; Doxorubicin; Drug Carriers; Drug Liberation; HEK293 Cells; Heterocyclic Compounds, 1-Ring; Humans; Nanoparticles; Polyethylene Glycols
PubMed: 27862818
DOI: 10.1002/cbic.201600560 -
International Journal of Molecular... Jun 2022Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug...
Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug doxorubicin. Therefore, we determined cell-substrate topology of cultivated CHO cells transfected with a membrane-associated Green Fluorescent Protein (GFP) in the nanometer range prior to and subsequent to the application of doxorubicin. Cell-substrate distances increased up to a factor of 2 after 24 h of application. A reduction of these distances by again a factor 2 was observed upon cell aging, and an influence of the cultivation time is presently discussed. Applicability of VA-TIRFM was supported by measurements of MCF-7 breast cancer cells after membrane staining and incubation with doxorubicin, when cell-substrate distances increased again by a factor ≥ 2. So far, our method needs well-defined cell ages and staining of cell membranes or transfection with GFP or related molecules. Use of intrinsic fluorescence or even light-scattering methods to various cancer cell lines could make this method more universal in the future, e.g., in the context of early detection of apoptosis.
Topics: Animals; Cell Membrane; Cricetinae; Cricetulus; Doxorubicin; Green Fluorescent Proteins; Microscopy, Fluorescence
PubMed: 35682954
DOI: 10.3390/ijms23116277 -
Molecules (Basel, Switzerland) Jun 2021Silica nanoparticles (SiO NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto...
Silica nanoparticles (SiO NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto the SiO NPs surfaces. The DOX·HCl loading onto and release from the SiO NPs was monitored via UV-VIS and fluorescence spectra. Alternatively, the zeta potential was also used to monitor and evaluate the DOX·HCl loading process. The results showed that nearly 98% of DOX·HCl was effectively loaded onto the SiO NPs' surfaces by electrostatic interaction. The pH-dependence of the process wherein DOX·HCl release out of DOX·HCl-SiO NPs was investigated as well. For comparison, both the free DOX·HCl molecules and DOX·HCl-SiO NPs were used as the labels for cultured cancer cells. Confocal laser scanning microscopy images showed that the DOX·HCl-SiO NPs were better delivered to cancer cells which are more acidic than healthy cells. We propose that engineered DOX·HCl-SiO systems are good candidates for drug delivery and clinical applications.
Topics: Antineoplastic Agents; Doxorubicin; Drug Carriers; Humans; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Neoplasms; Silicon Dioxide
PubMed: 34209621
DOI: 10.3390/molecules26133968 -
Biomedicine & Pharmacotherapy =... Sep 2023Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause...
Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p < 0.05) and proteins (FC > 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.
Topics: Humans; Mice; Animals; Cardiotoxicity; NAD; Doxorubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Myocytes, Cardiac; Mitochondria
PubMed: 37523986
DOI: 10.1016/j.biopha.2023.115232 -
Asian Pacific Journal of Cancer... Dec 2022Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and...
BACKGROUNDS
Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and therapeutic resistance ability. Quercetin is a popular flavonoid with lower adverse effects and has anti-tumor properties. Therefore, we assessed the anticancer activity of Quercetin and Doxorubicin alone and in combination in the T47D cells of human breast cancer and their isolated Cancer stem cells (CSCs).
MATERIALS AND METHODS
The human breast cancer cell line T47D was used for this experiment. T47D CSCs were isolated by magnetic bead sorting using the MACS system. The anticancer activity of Quercetin and Doxorubicin alone and in combination were evaluated using MTT cytotoxicity assay and cell cycle distribution and apoptosis induction by flow cytometry analysis.
RESULTS
We have shown that almost 1% of T47D cell populations are made up of CD44+/CD24- cells, which considered as cancer stem cells. Quercetin and Doxorubicin alone or in combination inhibited cell proliferation and induced apoptosis in breast cancer T47D cells and in lower extent in CD44+/CD24- cells. Quercetin significantly strengthened Doxorubicin's cytotoxicity and apoptosis induction in both cell populations. Quercetin and Doxorubicin and their combination induced G2/M arrest in the T47D cells and to a lesser extent in isolated CSCs. A value of p < 0.05 was considered as indicating a statistically significant difference.
CONCLUSION
These outcomes suggested that CSCs are a minor population of cancer cells, which play a significant role in drug resistance by being quiescent, slow cycling and resistance to apoptosis. Furthermore, our data showed that adding Quercetin to Doxorubicin is an effective approach for the treatment of both CSCs and bulk tumor cells.
Topics: Humans; Female; Quercetin; Apoptosis; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; Doxorubicin; Cell Cycle Checkpoints; Breast Neoplasms; Cell Proliferation; Cell Cycle; Neoplastic Stem Cells
PubMed: 36579996
DOI: 10.31557/APJCP.2022.23.12.4145