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Anti-cancer Agents in Medicinal... 2021Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of... (Review)
Review
Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.
Topics: Antibiotics, Antineoplastic; Cell Proliferation; Doxorubicin; Humans; Molecular Conformation; Nanoparticles; Neoplasms
PubMed: 33372884
DOI: 10.2174/1871520621666201229115612 -
International Journal of Biological... 2022Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its... (Review)
Review
Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.
Topics: Acute Disease; Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cell Death; Doxorubicin; Humans; Neoplasms; Oxidative Stress
PubMed: 35002523
DOI: 10.7150/ijbs.65258 -
European Review For Medical and... Jan 2020To investigate the influences of rapamycin on proliferation and apoptosis of human osteosarcoma MG-63 cells and the mechanisms of action.
OBJECTIVE
To investigate the influences of rapamycin on proliferation and apoptosis of human osteosarcoma MG-63 cells and the mechanisms of action.
MATERIALS AND METHODS
The human osteosarcoma MG-63 cells were randomly divided into Control group, Rapamycin group, and Rapamycin + Beclin-1 plasmid transfection group. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was adopted to detect the viability of MG-63 cells in each group, and the 5-Ethynyl-2'-deoxyuridine (EdU) staining and Hoechst staining were applied to determine the proliferation and apoptosis, respectively, of MG-63 cells in each group. The levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were measured using enzyme-linked immunosorbent assay (ELISA) kits, and the protein expression levels of Beclin-1 and Vps34 in each group of MG-63 cells were tested using the Western blotting.
RESULTS
Compared with the Control group, Rapamycin group, and Rapamycin + Beclin-1 plasmid transfection group had markedly weakened the viability of MG-63 cells, inhibited cell proliferation, remarkably increased cell apoptosis rate, elevated Bax level, notably declined Bcl-2 level, and significantly raised the levels of Beclin-1 and Vps34 proteins in MG-63 cells. Besides, the effects in Beclin-1 plasmid transfection group were stronger.
CONCLUSIONS
Rapamycin may decrease the viability, inhibit the proliferation, and promote the apoptosis of MG-63 cells by activating autophagy.
Topics: Antibiotics, Antineoplastic; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Osteosarcoma; Random Allocation; Sirolimus
PubMed: 32016998
DOI: 10.26355/eurrev_202001_20076 -
Clinical Science (London, England :... May 2021Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is... (Review)
Review
Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced cardiovascular toxicity.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular System; Humans; Myocytes, Cardiac; Risk Factors
PubMed: 34047339
DOI: 10.1042/CS20200301 -
Biomedicine & Pharmacotherapy =... Sep 2021Tranilast (TRN) or (N-3,4 -dimethoxy cinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite and is identified mainly as an anti-allergic agent with limited... (Review)
Review
Tranilast (TRN) or (N-3,4 -dimethoxy cinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite and is identified mainly as an anti-allergic agent with limited side effects. The anti-cancer effects of tranilast either alone or in combination with chemotherapeutic drugs have been evidenced in several pre-clinical studies. The main mechanism of action of tranilast includes targeting and modulation of various signaling and immune regulatory pathways including Transforming growth factor-beta (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol 3-kinase (PI3K), MAP-Kinase (MAPK), Protein kinase B (Akt/PKB), c-Jun N-terminal kinase, modulation of cancer stem cells, etc. Most of these pathways are involved in tumor proliferation, invasion, and metastasis and it is postulated that tranilast, with its low toxicity profile and high anti-carcinogenic abilities, can serve as a potential anti-tumorigenic agent. The main aim of this review is to provide updated information on the anti-cancer effects of tranilast and its significance as a therapeutic agent.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Neoplasms; Signal Transduction; ortho-Aminobenzoates
PubMed: 34174504
DOI: 10.1016/j.biopha.2021.111844 -
International Journal of Environmental... Apr 2022(1) Background: Anthracyclines are intriguing drugs, representing one of the cornerstones of both first and subsequent-lines of chemotherapy in ovarian cancer (OC).... (Review)
Review
(1) Background: Anthracyclines are intriguing drugs, representing one of the cornerstones of both first and subsequent-lines of chemotherapy in ovarian cancer (OC). Their efficacy and mechanisms of action are related to the hot topics of OC clinical research, such as BRCA status and immunotherapy. Prediction of response to anthracyclines is challenging and no markers can predict certain therapeutic success. The current narrative review provides a summary of the clinical and biological mechanisms involved in the response to anthracyclines. (2) Methods: A MEDLINE search of the literature was performed, focusing on papers published in the last two decades. (3) Results and Conclusions: BRCA mutated tumors seem to show a higher response to anthracyclines compared to sporadic tumors and the severity of hand-foot syndrome and mucositis may be a predictive marker of PLD efficacy. CA125 can be a misleading marker of clinical response during treatment with anthracyclines, the response of which also appears to depend on OC histology. Immunochemistry, in particular HER-2 expression, could be of some help in predicting the response to such drugs, and high levels of mutated p53 appear after exposure to anthracyclines and impair their antitumor effect. Finally, organoids from OC are promising for drug testing and prediction of response to chemotherapy.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Ovarian Epithelial; Doxorubicin; Humans; Ovarian Neoplasms; Polyethylene Glycols
PubMed: 35409939
DOI: 10.3390/ijerph19074260 -
Future Oncology (London, England) Apr 2020In recent, intra- and inter-tumor heterogeneity is seen as one of key factors behind success and failure of chemotherapy. Incessant use of doxorubicin (DOX) drug is... (Review)
Review
In recent, intra- and inter-tumor heterogeneity is seen as one of key factors behind success and failure of chemotherapy. Incessant use of doxorubicin (DOX) drug is associated with numerous post-treatment debacles including cardiomyopathy, health disorders, reversal of tumor and formation of secondary tumors. The module of cancer treatment has undergone evolutionary changes by achieving crucial understanding on molecular, genetic, epigenetic and environmental adaptations by cancer cells. Therefore, there is a paradigm shift in cancer therapeutic by employing amalgam of peptide mimetic, small RNA mimetic, DNA repair protein inhibitors, signaling inhibitors and epigenetic modulators to achieve targeted and personalized DOX therapy. This review summarizes on recent therapeutic avenues that can potentiate DOX effects by removing discernible pitfalls among cancer patients.
Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; DNA Repair; Doxorubicin; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 32253930
DOI: 10.2217/fon-2019-0458 -
Chembiochem : a European Journal of... Nov 2021To overcome high toxicity, low bioavailability and poor water solubility of chemotherapeutics, a variety of drug carriers have been designed. However, most carriers are...
To overcome high toxicity, low bioavailability and poor water solubility of chemotherapeutics, a variety of drug carriers have been designed. However, most carriers are severely limited by low drug loading capacity and adverse side effects. Here, a new type of metal-drug nanoparticles (MDNs) was designed and synthesized. The MDNs self-assembled with Fe(III) ions and drug molecules through coordination, resulting in nanoparticles with high drug loading. To assist systemic delivery and prolong circulation time, the obtained MDNs were camouflaged with red blood cell (RBCs) membranes (RBCs@Fe-DOX MDNs) to improve their stability and dispersity. The RBCs@Fe-DOX MDNs presented pH-responsive release functionalities, resulting in drug release accelerated in acidic tumor microenvironments. The outstanding in vitro and in vivo antitumor therapeutic outcome was realized by RBCs@Fe-DOX MDNs. This study provides an innovative design guideline for chemotherapy and demonstrates the great capacity of nanomaterials in anticancer treatments.
Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; Doxorubicin; Drug Screening Assays, Antitumor; Erythrocytes; Ferric Compounds; Hydrogen-Ion Concentration; Mice; Molecular Structure; Nanoparticles; Neoplasms, Experimental; Particle Size
PubMed: 34468067
DOI: 10.1002/cbic.202100313 -
Journal of Experimental & Clinical... Apr 2022Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain...
BACKGROUND
Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated.
METHODS
Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy.
RESULTS
We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin.
CONCLUSIONS
Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.
Topics: Adolescent; Animals; Antibiotics, Antineoplastic; Bone Neoplasms; Clustered Regularly Interspaced Short Palindromic Repeats; DNA-Binding Proteins; Doxorubicin; Humans; Mice; Osteosarcoma; Ubiquitin-Protein Ligases
PubMed: 35459258
DOI: 10.1186/s13046-022-02344-y -
Bioorganic Chemistry Jul 2023The DNA topoisomerase enzymes are widely distributed throughout all spheres of life and are necessary for cell function. Numerous antibacterial and cancer... (Review)
Review
The DNA topoisomerase enzymes are widely distributed throughout all spheres of life and are necessary for cell function. Numerous antibacterial and cancer chemotherapeutic drugs target the various topoisomerase enzymes because of their roles in maintaining DNA topology during DNA replication and transcription. Agents derived from natural products, like anthracyclines, epipodophyllotoxins and quinolones, have been widely used to treat a variety of cancers. A very active field of fundamental and clinical research is the selective targeting of topoisomerase II enzymes for cancer treatment. This thematic review summarizes the recent advances in the anticancer activity of the most potent topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins and fluoroquinolones) their modes of action, and structure-activity relationships (SARs) organized chronologically in the last ten years from 2013 to 2023. The review also highlights the mechanism of action and SARs of promising new topoisomerase II inhibitors.
Topics: Topoisomerase II Inhibitors; Antineoplastic Agents; Antibiotics, Antineoplastic; DNA Topoisomerases, Type II; Podophyllotoxin; Anthracyclines; Topoisomerase I Inhibitors
PubMed: 37094479
DOI: 10.1016/j.bioorg.2023.106548