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Journal of Molecular Graphics &... Nov 2023In the present work, the drug-loading efficacy of graphyne (GYN) for doxorubicin (DOX) drug is investigated for the first time by using density functional theory (DFT)....
In the present work, the drug-loading efficacy of graphyne (GYN) for doxorubicin (DOX) drug is investigated for the first time by using density functional theory (DFT). Doxorubicin drug is effective in the cure of numerous types of cancer including bone cancer, gastric, thyroid, bladder, ovarian, breast, and soft tissue cancer. Doxorubicin drug prevents the cell division process by intercalating in the double-helix of DNA and stopping its replication. The optimized, geometrical, energetic, and excited-state characteristics of graphyne (GYN), doxorubicin drug (DOX), and doxorubicin-graphyne complex (DOX@GYN complex) are calculated to see how effective it is as a carrier. The DOX drug interacted with GYN with an adsorption-energy of -1.57 eV (gas-phase). The interaction of GYN with DOX drug is investigated using NCI (non-covalent interaction) analysis. The findings of this analysis showed that the DOX@GYN complex has weak forces of interaction. Charge transfer from doxorubicin drug to GYN during DOX@GYN complex formation is described by charge-decomposition analysis and HOMO-LUMO analysis. The increased dipole-moment (8.41 D) of the DOX@GYN in contrast with therapeutic agent DOX and GYN indicated that the drug will move easily in the biochemical system. Furthermore, the photo-induced electron-transfer process is explored for excited states, and it reveals that upon interaction, fluorescence-quenching will occur in the complex DOX@GYN. In addition, the influence of the positive and negative charge states on the GYN and DOX@GYN is also considered. Overall, the findings indicated that the GYN could be exploited as an effective drug-transporter for the delivery of doxorubicin drug. Investigators will be inspired to look at another 2D nanomaterials for drug transport applications as a result of this theoretical work.
Topics: Humans; Drug Carriers; Doxorubicin; Drug Delivery Systems; Neoplasms; Nanostructures; Cell Line, Tumor
PubMed: 37321062
DOI: 10.1016/j.jmgm.2023.108537 -
The Journal of Antibiotics Sep 1994Doxorubicin-gamma-cyclodextrin conjugates have been synthesized by the coupling of 14-bromodaunomycin with mono half-ester compounds linked to a 6-hydroxyl group of... (Comparative Study)
Comparative Study
Doxorubicin-gamma-cyclodextrin conjugates have been synthesized by the coupling of 14-bromodaunomycin with mono half-ester compounds linked to a 6-hydroxyl group of gamma-cyclodextrin. Release of drug from the conjugates in saline phosphate buffer solution and in vitro antitumor activity against L1210 leukemia cells were also investigated.
Topics: Animals; Cyclodextrins; Doxorubicin; Drug Carriers; Leukemia L1210
PubMed: 7928690
DOI: 10.7164/antibiotics.47.1025 -
Scientific Reports Jul 2017Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance...
Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin's interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn't impair doxorubicin's membrane partitioning, but reduces drug's influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Membrane; Cholesterol; Computational Biology; Computer Simulation; Doxorubicin; Membrane Fluidity; Membranes, Artificial; Models, Molecular; Molecular Dynamics Simulation; Spectrophotometry, Ultraviolet
PubMed: 28740256
DOI: 10.1038/s41598-017-06445-z -
Cell Cycle (Georgetown, Tex.) 2015Genomic screens of doxorubicin toxicity in S. cerevisiae have identified numerous mutants in amino acid and carbon metabolism which express increased doxorubicin...
Genomic screens of doxorubicin toxicity in S. cerevisiae have identified numerous mutants in amino acid and carbon metabolism which express increased doxorubicin sensitivity. This work examines the effect of amino acid metabolism on doxorubicin toxicity. S. cerevisiae were treated with doxorubicin in combination with a variety of amino acid supplements. Strains of S. cerevisiae with mutations in pathways utilizing aspartate and other metabolites were examined for sensitivity to doxorubicin. S. cerevisiae cultures exposed to doxorubicin in minimal media showed significantly more toxicity than cultures exposed in rich media. Supplementing minimal media with aspartate, glutamate or alanine reduced doxorubicin toxicity. Cell cycle response was assessed by examining the budding pattern of treated cells. Cultures exposed to doxorubicin in minimal media arrested growth with no apparent cell cycle progression. Aspartate supplementation allowed cultures exposed to doxorubicin in minimal media to arrest after one division with a budding pattern and survival comparable to cultures exposed in rich media. Aspartate provides less protection from doxorubicin in cells mutant in either mitochondrial citrate synthase (CIT1) or NADH oxidase (NDI1), suggesting aspartate reduces doxorubicin toxicity by facilitating mitochondrial function. These data suggest glycolysis becomes less active and mitochondrial respiration more active following doxorubicin exposure.
Topics: Aspartic Acid; Cell Survival; Cells, Cultured; Doxorubicin; Growth Inhibitors; Mitochondria; Saccharomyces cerevisiae
PubMed: 26317891
DOI: 10.1080/15384101.2015.1087619 -
British Journal of Cancer Jul 2003Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against...
Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) doxorubicin with(out) monoHER (0.2-1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC(50)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (< or =25 micro M, P<0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in vivo.
Topics: Antineoplastic Agents; Cell Adhesion; Cell Culture Techniques; Dose-Response Relationship, Drug; Doxorubicin; Endothelium, Vascular; Hydroxyethylrutoside; Inflammation; Neutrophils; Umbilical Cord
PubMed: 12865930
DOI: 10.1038/sj.bjc.6601022 -
International Journal of Biological... Jun 2023Removing residual tumor cells around bone tissue and promoting bone defect repair pose significant challenges after osteosarcoma resection. Herein, we designed an...
Removing residual tumor cells around bone tissue and promoting bone defect repair pose significant challenges after osteosarcoma resection. Herein, we designed an injectable multifunctional hydrogel therapeutic platform for synergistic photothermal chemotherapy of tumors and promoting osteogenesis. In this study, the black phosphorus nanosheets (BPNS) and doxorubicin (DOX) were encapsulated in an injectable chitosan-based hydrogel (BP/DOX/CS). The BP/DOX/CS hydrogel exhibited excellent photothermal effects under NIR irradiation due to incorporating BPNS. The prepared hydrogel has good drug-loading capacity and can continuously release DOX. In addition, K7M2-WT tumor cells are effectively eliminated under the combined effect of chemotherapy and photothermal stimulation. Furthermore, the BP/DOX/CS hydrogel has good biocompatibility and promotes osteogenic differentiation of MC3T3-E1 cells by releasing phosphate. In vivo results also confirmed that the BP/DOX/CS hydrogel can be injected at the tumor site to eliminate the tumor efficiently without systemic toxicity. This easily prepared multifunctional hydrogel with a synergistic photothermal-chemotherapy effect has excellent potential for clinically treating bone-related tumors.
Topics: Humans; Hydrogels; Osteogenesis; Phosphorus; Doxorubicin; Bone Neoplasms; Cell Line, Tumor
PubMed: 36972826
DOI: 10.1016/j.ijbiomac.2023.124209 -
Journal of Bioenergetics and... Aug 2018The clinical management of anaplastic thyroid carcinoma and follicular thyroid carcinoma is challenging and requires an alternative therapeutic strategy. Although...
The clinical management of anaplastic thyroid carcinoma and follicular thyroid carcinoma is challenging and requires an alternative therapeutic strategy. Although atovaquone is an FDA-approved anti-malarial drug, studies has recently demonstrated its anti-cancer activities. In line with these efforts, our study shows that atovaquone is an attractive candidate for thyroid cancer treatment. We show that atovaquone significantly inhibits growth, migration and survival in a concentration-dependent manner in 8505C and FTC113 cells. Mechanistically, atovaquone inhibits mitochondrial complex III activity, leading to mitochondrial respiration inhibition and reduction of ATP production in thyroid cancer cells. The inhibitory effects of atovaquone is reversed in mitochondrial respiration-deficient 8505C ρ0 cells, confirming mitochondrial respiration as the mechanism of atovaquone's action in thyroid cancer. In addition, atovaquone suppresses phosphorylation of STAT3 in thyroid cancer wildype but not ρ0 cells, demonstrating that STAT3 phosphorylation inhibition by atovaquone is a consequence of mitochondrial respiration inhibition. Notably, we further demonstrate that atovaquone significantly augments doxorubicin's inhibitory effects via suppressing mitochondrial respiration and STAT3. Our findings suggest that atovaquone can be repurposed for thyroid cancer treatment. Our work also highlights that targeting mitochondrial respiration may represent potential therapeutic strategy in thyroid cancer.
Topics: Atovaquone; Cell Line; Cell Line, Tumor; Cell Respiration; Cell Survival; Doxorubicin; Drug Synergism; Humans; Mitochondria; Phosphorylation; STAT3 Transcription Factor; Thyroid Neoplasms
PubMed: 29687367
DOI: 10.1007/s10863-018-9755-y -
Annals of Internal Medicine Sep 1974
Topics: Doxorubicin; Humans; Liver; Neoplasms
PubMed: 4850444
DOI: 10.7326/0003-4819-81-3-414 -
Advanced Science (Weinheim,... Apr 2022Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new...
Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote-controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US-controlled drug activation strategy, herein a mechano-responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof-of-concept, the synthesis, characterization, and US-responsive drug activation evaluation of the mechano-nanoswitch, which provides a blueprint for tailoring nanosystems for force-induced pharmacotherapy is presented.
Topics: Activation, Metabolic; Doxorubicin; Drug Liberation; Humans; Macromolecular Substances; Neoplasms
PubMed: 35195372
DOI: 10.1002/advs.202104696 -
Analytical Chemistry Dec 2022Target identification is critically important for understanding the mechanism of action of drugs. Here, we reported a new strategy for deconvolution of drug targets (or...
Target identification is critically important for understanding the mechanism of action of drugs. Here, we reported a new strategy for deconvolution of drug targets (or off-targets) with photoaffinity labeling chemoproteomics in combination with untargeted metabolomics by using doxorubicin (DOX) as a model. The DOX-derived photoaffinity probes were prepared and applied to capture DOX-interacting proteins in living cells. The captured DOX-interacting proteins were then identified by label-free quantitative proteomics. Totally, 151 significant proteins were identified with high confidence (fold change >4, -value < 0.005). The gene ontology enrichment analysis suggested that the proteins were mainly involved in carbon metabolism, citrate cycle, fatty acid metabolism, and metabolic pathways. Therefore, untargeted metabolomics was applied to quantify the significantly altered metabolites in cells upon drug treatment. The pathway enrichment analysis suggested that DOX mainly interrupted with the processes of pyrimidine and purine metabolism, carbon metabolism, methionine metabolism, and phosphatidylcholine biosynthesis. Integrative analysis of chemoproteomics and metabolomics indicated that adenosylhomocysteinase (AHCY) is a new target (off-target) of DOX leading to the accumulation of S-adenosyl homocysteine. This deduced DOX target was confirmed by the cellular thermal shift assay, affinity competitive pull-down assay, biochemical assay, and siRNA knock down experiments. Our result suggested that AHCY is the uncovered off-target of DOX.
Topics: Metabolomics; Doxorubicin; Metabolic Networks and Pathways; Lipid Metabolism; Carbon
PubMed: 36445716
DOI: 10.1021/acs.analchem.2c03377