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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 -
Molecular Aspects of Medicine Oct 2023Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by... (Review)
Review
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
Topics: Humans; Anthracyclines; Drug Resistance, Neoplasm; Doxorubicin; Antibiotics, Antineoplastic; Neoplasms
PubMed: 37515939
DOI: 10.1016/j.mam.2023.101205 -
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 -
Cells Feb 2023Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, the precise mechanisms of DOX's action are not... (Review)
Review
Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, the precise mechanisms of DOX's action are not fully understood. Emerging evidence points to the pleiotropic anticancer activity of DOX, including its contribution to DNA damage, reactive oxygen species (ROS) production, apoptosis, senescence, autophagy, ferroptosis, and pyroptosis induction, as well as its immunomodulatory role. This review aims to collect information on the anticancer mechanisms of DOX as well as its influence on anti-tumor immune response, providing a rationale behind the importance of DOX in modern cancer therapy.
Topics: Humans; Doxorubicin; Apoptosis; Reactive Oxygen Species; Autophagy; Neoplasms
PubMed: 36831326
DOI: 10.3390/cells12040659 -
Nature Communications Oct 2022Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an...
Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviates immune dysregulation and attenuates lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Humans; Immunosuppression Therapy; Lung Neoplasms; Neoplasm Recurrence, Local; Triple Negative Breast Neoplasms
PubMed: 36184683
DOI: 10.1038/s41467-022-33598-x -
Nature Communications Sep 2023Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals...
Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals that induce phase transition within chromatin at the microscale. This microscopic screening approach reveals that adriamycin (doxorubicin) - a widely used anticancer drug that is known to interact with chromatin - specifically induces visible local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments systematically and quantitatively demonstrate that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces phase transition of H1, forming fibrous aggregates in vitro. These results reveal a phase separation-driven mechanism for a chemotherapeutic drug.
Topics: Chromatin; Biomolecular Condensates; Chromatin Immunoprecipitation Sequencing; Doxorubicin; Gene Expression Profiling
PubMed: 37689690
DOI: 10.1038/s41467-023-41340-4 -
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 -
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 -
ESMO Open Feb 2022We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed...
BACKGROUND
We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients.
PATIENTS AND METHODS
Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained.
RESULTS
There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome.
CONCLUSIONS
We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).
Topics: Brain Neoplasms; Doxorubicin; ErbB Receptors; Glioblastoma; Humans; Liposomes
PubMed: 34998092
DOI: 10.1016/j.esmoop.2021.100365 -
International Journal of Molecular... Nov 2017Nitroxides are stable free radicals that contain a nitroxyl group with an unpaired electron. In this paper, we present the properties and application of nitroxides as... (Review)
Review
Nitroxides are stable free radicals that contain a nitroxyl group with an unpaired electron. In this paper, we present the properties and application of nitroxides as antioxidants and anticancer drugs. The mostly used nitroxides in biology and medicine are a group of heterocyclic nitroxide derivatives of piperidine, pyrroline and pyrrolidine. The antioxidant action of nitroxides is associated with their redox cycle. Nitroxides, unlike other antioxidants, are characterized by a catalytic mechanism of action associated with a single electron oxidation and reduction reaction. In biological conditions, they mimic superoxide dismutase (SOD), modulate hemoprotein's catalase-like activity, scavenge reactive free radicals, inhibit the Fenton and Haber-Weiss reactions and suppress the oxidation of biological materials (peptides, proteins, lipids, etc.). The use of nitroxides as antioxidants against oxidative stress induced by anticancer drugs has also been investigated. The application of nitroxides and their derivatives as anticancer drugs is discussed in the contexts of breast, hepatic, lung, ovarian, lymphatic and thyroid cancers under in vivo and in vitro experiments. In this article, we focus on new natural spin-labelled derivatives such as camptothecin, rotenone, combretastatin, podophyllotoxin and others. The applications of nitroxides in the aging process, cardiovascular disease and pathological conditions were also discussed.
Topics: Aging; Animals; Antineoplastic Agents; Antioxidants; Disease Susceptibility; Doxorubicin; Humans; Neoplasms; Nitrogen Oxides; Oxidation-Reduction; Oxidative Stress; Superoxide Dismutase
PubMed: 29165366
DOI: 10.3390/ijms18112490