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Apoptosis : An International Journal on... Jun 2024Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as...
Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.
Topics: Doxorubicin; Myocytes, Cardiac; Sirtuin 1; Animals; Cellular Senescence; Poly(ADP-ribose) Polymerases; Rats; Cardiotoxicity; Apoptosis; Rats, Sprague-Dawley; Antibiotics, Antineoplastic; Cardiomyopathies; Humans
PubMed: 38281279
DOI: 10.1007/s10495-023-01929-y -
Structure (London, England : 1993) May 2021ETS family transcription factors of ERG and FLI1 play a key role in oncogenesis of prostate cancer and Ewing sarcoma by binding regulatory DNA sites and interfering with...
ETS family transcription factors of ERG and FLI1 play a key role in oncogenesis of prostate cancer and Ewing sarcoma by binding regulatory DNA sites and interfering with function of other factors. Mithramycin (MTM) is an anti-cancer, DNA binding natural product that functions as a potent antagonist of ERG and FLI1 by an unknown mechanism. We present a series of crystal structures of the DNA binding domain (DBD) of ERG/FLI1 culminating in a structure of a high-order complex of the ERG/FLI1 DBD, transcription factor Runx2, core-binding factor beta (Cbfβ), and MTM on a DNA enhancer site, along with supporting DNA binding studies using MTM and its analogues. Taken together, these data provide insight into allosteric mechanisms underlying ERG and FLI1 transactions and their disruption by MTM analogues.
Topics: Allosteric Regulation; Antibiotics, Antineoplastic; Binding Sites; Core Binding Factor Alpha 1 Subunit; Core Binding Factor beta Subunit; Humans; Molecular Docking Simulation; Plicamycin; Protein Binding; Proto-Oncogene Protein c-fli-1; Transcriptional Regulator ERG
PubMed: 33275876
DOI: 10.1016/j.str.2020.11.012 -
Bioorganic & Medicinal Chemistry Sep 2021Epidermal growth factor receptor (EGFR) is overexpressed in many cancers and therefore serves as an excellent target for prodrug activation. Functionalised...
Epidermal growth factor receptor (EGFR) is overexpressed in many cancers and therefore serves as an excellent target for prodrug activation. Functionalised trans-cyclooctenes (TCO) were conjugated to an EGFR antibody (cetuximab), providing a reagent for pre-targeting and localisation of the bioorthogonal reagent. The TCOs react with a 4-azidobenzyl carbamate doxorubicin prodrug via a [3 + 2]-cycloaddition and subsequent self-immolation leads to release of doxorubicin (click-and-release). In vitro cell-based assays demonstrated proof-of-concept, that cetuximab conjugated to highly strained TCO (AB-d-TCO) could bind to the EGFR in a melanoma cell line, and selectively activate the doxorubicin prodrug. In a non-EGFR expressing melanoma cell line, no significant prodrug activation was observed. In vivo experiments using this combination of AB-d-TCO and the azido-doxorubicin prodrug in a murine melanoma model revealed no significant anti-tumour activity or increased survival, suggesting there was insufficient prodrug activation and drug release at the tumour site.
Topics: Alkenes; Animals; Antibiotics, Antineoplastic; Azides; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Humans; Mice; Mice, Inbred C57BL; Molecular Structure; Prodrugs; Protein Kinase Inhibitors; Structure-Activity Relationship
PubMed: 34411983
DOI: 10.1016/j.bmc.2021.116361 -
Arquivos Brasileiros de Cardiologia 2024
Topics: Humans; Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Polyketides
PubMed: 38451618
DOI: 10.36660/abc.20230821 -
Advanced Drug Delivery Reviews 2020Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by... (Review)
Review
Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by transmembrane ion gradients. An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a mitomycin c-derived lipidic prodrug (MLP) which is entrapped in the bilayer of PEGylated liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional chemotherapy in various tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of tumor growth is related to the enhanced tumor localization of long-circulating liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in chemoradiotherapy, where it has shown a strong radiosensitizing effect in animal models based on a unique mechanism of enhanced prodrug activation and encouraging results in early human testing.
Topics: Animals; Antibiotics, Antineoplastic; Humans; Lipids; Liposomes; Mitomycin; Neoplasms; Polyethylene Glycols; Prodrugs; Tissue Distribution; Treatment Outcome
PubMed: 32777239
DOI: 10.1016/j.addr.2020.07.027 -
The Journal of Knee Surgery Feb 2020As the number of total joint arthroplasties continues to rise, periprosthetic joint infection (PJI), a significant and devastating complication of total joint... (Review)
Review
As the number of total joint arthroplasties continues to rise, periprosthetic joint infection (PJI), a significant and devastating complication of total joint arthroplasty, may also increase. In PJI, bacterial biofilms are formed by causative pathogens surrounded by extracellular matrix with relatively dormant cells that can persist, resulting in a barrier against the host immune system and antibiotics. These biofilms not only contribute to the pathogenesis of PJI but also result in diagnostic challenges, antibiotic resistance, and PJI treatment failure. This review discusses the development of biofilms and key features associated with biofilm pathogenicity in PJI, current PJI diagnostic methods and their limitations, and current treatment options. Additionally, this article explores novel approaches to treat PJI, including targeting persister bacteria, immunotherapy, antimicrobial peptides, nanoparticles, and bacteriophage therapy. Biofilm eradication can also be achieved through enzymatic therapy, photodynamic therapy, and ultrasound. Finally, this review discusses novel techniques to prevent PJI, including improved irrigation solutions, smart implants with antimicrobial properties, inhibition of quorum sensing, and vaccines, which may revolutionize PJI management in the future by eradicating a devastating problem.
Topics: Anti-Infective Agents; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Biofilms; Humans; Immunotherapy; Nanoparticles; Phage Therapy; Photochemotherapy; Prosthesis-Related Infections; Quorum Sensing; Ultrasonic Therapy; Vaccines
PubMed: 31935760
DOI: 10.1055/s-0040-1701214 -
Cucurbit[n]uril-based amphiphiles that self-assemble into functional nanomaterials for therapeutics.Chemical Communications (Cambridge,... Sep 2019Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various... (Review)
Review
Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.
Topics: Antibiotics, Antineoplastic; Bridged-Ring Compounds; Cell Proliferation; Doxorubicin; HeLa Cells; Humans; KB Cells; Nanostructures; Surface-Active Agents
PubMed: 31418758
DOI: 10.1039/c9cc05567c -
Vascular Health and Risk Management 2022Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial...
BACKGROUND
Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial deterioration, and direct repression of muscle-specific gene expression. Adriamycin (Doxorubicin) is a potent anti-cancer agent. Adriamycin in prolonged use is fatal and generates free radicals that lead to dose-dependent cardiac toxicity.
OBJECTIVE
The intent of the study was to explore the protective activity of candesartan and quercetin in cardiomyopathy induced by doxorubicin in rats.
METHODS
To induce cardiac toxicity, rats were intraperitoneally treated with doxorubicin (06 equivalent injections of 2.5 mg/kg, i. p. at 48 hour interval for 02 consecutive weeks to achieve a cumulative dose of 15 mg/kg). Individual and combined oral treatment of candesartan (5 mg/kg/day) and quercetin (10 mg/kg/day) was administered for four weeks.
RESULTS
Following cardiomyopathy, heart/body weight ratio (3.526 × 10), serum creatine kinase (352.4±16.99 IU/L), lactate dehydrogenase (661.7±20.45 IU/L) levels were elevated in addition to altered lipid profile (TC - 118.4±4.25 mg/dL, TG - 263.3±9.99 mg/dL, VLDL - 52.66±1.99 mg/dL, LDL - 52.99±5.80 mg/dL and HDL - 12.78±0.36 mg/dL). The pre-cotreatment of candesartan and quercetin significantly restored the values to normal. The increased level of lipid peroxides (33.12±1.63 µmol/mg protein), serum troponin-T (1.82 ± 0.11 pg/mL) and nitric oxide (13.33±0.73 nmol/mg protein) level along with attenuating antioxidant profile, ie catalase, glutathione and superoxide dismutase (1.43±0.12 nmol/mg protein, 8.48±0.42 nmol/mg protein and 2.09±0.031 U/mg protein) were reversed to normal. Morphometry and histopathologic changes represented a beneficial effect of single and combination pre-cotreatment of drugs which significantly decreases adriamycin cardiac toxicity.
CONCLUSION
The overall result depicts more beneficial and cardioprotective effect of quercetin and candesartan combination as compared to their individual effects in doxorubicin treated animals. Therefore, this combination might be a suitable option to treat the cardiotoxic effect of doxorubicin.
Topics: Humans; Rats; Animals; Cardiotoxicity; Quercetin; Doxorubicin; Myocardium; Antioxidants; Antibiotics, Antineoplastic; Cardiomyopathies; Oxidative Stress
PubMed: 36536768
DOI: 10.2147/VHRM.S381485 -
Angewandte Chemie (International Ed. in... Sep 2021The combination of gene therapy and chemotherapy provides a We developed a simple and versatile approach to prepare a series of two-in-one nanodrugs through direct...
The combination of gene therapy and chemotherapy provides a We developed a simple and versatile approach to prepare a series of two-in-one nanodrugs through direct self-assembly of cyanine-labeled single-stranded DNA (Cys-DNA) and different types of drug molecules. Molecular dynamics simulation showed that the Cys introduced into the DNA could enhance the noncovalent interaction between Cys-DNA and drug molecules. More drug molecules were incorporated into Cys-DNA, tending to spontaneously form hybrid Cys-DNA/drug nanosphere. Such nanospheres serve as both carriers and cargoes, excluding the extra use of nontherapeutic excipients and showing ultrahigh drug loading capacity. Following this approach, an antisense oligonucleotides/doxorubicin nanodrug model was constructed, demonstrating the significant synergistic anti-tumor therapeutic effect. As a proof of the concept, our study establishes a simple and reproducible two-in-one nucleic acid-based drug formulation.
Topics: Antibiotics, Antineoplastic; Carbocyanines; Cell Line, Tumor; Cell Survival; DNA; Doxorubicin; Drug Screening Assays, Antitumor; Humans; Molecular Dynamics Simulation; Nanoparticles; Oligonucleotides, Antisense; Particle Size
PubMed: 34296814
DOI: 10.1002/anie.202108393 -
Drug Delivery Dec 2022The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based...
The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based DOX-loaded implant and to evaluate the efficacy and drug metabolism distribution of the implant in intratumoral chemotherapy for osteosarcoma (OS). In this study, implants containing DOX, poly(d,l-lactide-co-glycolide), and polyethylene glycol 4000 were prepared by melt-molding method. Then, the antitumor activity and systemic drug distribution of the implants were tested in a K7M2 OS bearing mouse model. The scanning electron microscope images showed that DOX was uniformly dispersed in the polymer matrix. Both the and release profiles of implants are characterized by three-phase release. Implantation of DOX-loaded implants into tumors can inhibit tumor growth in a dose-dependent manner. The pharmacokinetic behavior shows that intratumor chemotherapy through implants has a much higher drug concentration in tumors than in normal tissues, which may be the reason for improving antitumor activity and reducing systemic side effects. In summary, the drug release of the implants prepared in this study is sustained and stable, which promotes long-term local accumulation of drugs in tumors, improves the efficacy of chemotherapy and has low toxicity to normal tissues.
Topics: Animals; Animals, Outbred Strains; Antibiotics, Antineoplastic; Bone Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Implants; Drug Liberation; Female; Male; Mice; Mice, Inbred BALB C; Osteosarcoma; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Random Allocation; Rats, Sprague-Dawley; Technology, Pharmaceutical; Xenograft Model Antitumor Assays; Rats
PubMed: 35147071
DOI: 10.1080/10717544.2022.2032878