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1.
Carbohydr Polym ; 300: 120233, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36372473

RESUMO

A novel delivery system based on linolenic acid (LA) conjugated chitosan (CS) polymeric micelles were proposed for improving the oral absorption of doxorubicin (DOX) through targeting intestinal fatty acid transporter. LA, as a ligand of the transporter, was grafted into CS to construct CS-LA micelles, and DOX was encapsulated into the micelles. The synthesized micelle material was identified by 1H NMR and FT-IR. The micelles showed regular spherical shapes with a particle size of 117.1 ± 1.6 nm, drug loading of 8.77 ± 0.02 %, and critical micelle concentration (CMC) of 23.6 µg/ml. The pharmacokinetics studies showed the relative bioavailability of 166 % versus DOX·HCl. The fatty acid transport protein 4-mediated intestinal uptake process of micelles was confirmed by the intracellular uptake, immunofluorescent imaging and permeation test. These findings confirmed the potential of CS-LA micelles as an effective oral delivery vehicle, and fatty acid transporter as a target spot for enhancing intestinal drug absorption.


Assuntos
Quitosana , Micelas , Quitosana/química , Ácido alfa-Linolênico , Ácidos Graxos , Espectroscopia de Infravermelho com Transformada de Fourier , Portadores de Fármacos/química , Doxorrubicina/química
2.
J Colloid Interface Sci ; 629(Pt A): 173-181, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36081202

RESUMO

HYPOTHESIS: Colloids with rough topography demonstrate more complex interactions and tremendous potential in industrial applications. However, relevant studies suffer from a range of challenges, including cumbersome synthesis, complex characterization, and very limited functionalities. A comprehensive study of rough nanoparticles can not only broaden our understanding of rough colloids, but also help to avoid some of their detrimental impacts in real life (e.g., clogging and pumping failures in slurry processing). EXPERIMENTS: A facile route to precisely control the surface roughness of silica nanoparticles and a highly efficient method to characterize the surface roughness were developed respectively. The fabricated particles can be applied for the immobilization of metal nanostructures; their cytotoxic effects and the capability to be used as a drug-delivery vehicle were also evaluated. FINDINGS: Modifying the addition time of precursors (i.e., TEOS and MPTMS) can precisely control the surface roughness of silica nanoparticles. The developed characterization method based on TEM observations allows statistical analyses on a large number of particles, and therefore features very reasonable accuracy. These rough particles behave like microporous materials, where the loading strategy is closely related to their surface roughness. Medium rough particles are promising carriers of metal nanostructures, while the roughest ones are excellent candidate for doxorubicin delivery to cancer cells.


Assuntos
Nanopartículas , Dióxido de Silício , Dióxido de Silício/química , Nanopartículas/química , Doxorrubicina/farmacologia , Coloides/química , Sistemas de Liberação de Medicamentos
3.
Gene ; 850: 146930, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36195266

RESUMO

Resistance to cancer therapeutics represents a leading cause of mortality and is particularly important in cancers, such as triple negative breast cancer, for which no targeted therapy is available, as these are only treated with traditional chemotherapeutics. Cancer, as well as bacterial, drug resistance can be intrinsic, acquired or adaptive. Adaptive cancer drug resistance is gaining attention as a mechanism for the generation of long-term drug resistance as is the case with bacterial antibiotic resistance. We have used a cellular model of triple negative breast cancer (CAL51) and its drug resistance derivative (CALDOX) to gain insight into genome-wide expression changes associated with long-term doxorubicin (a widely used anthracycline for cancer treatment) resistance and doxorubicin-induced stress. Previous work indicates that both naïve and resistance cells have a functional p53-p21 axis controlling cell cycle at G1, although this is not a driver for drug resistance, but down-regulation of TOP2A (topoisomerase IIα). As expected, CALDOX cells have a signature characterized, in addition to down-regulation of TOP2A, by genes and pathways associated with drug resistance, metastasis and stemness. Both CAL51 and CALDOX stress signatures share 12 common genes (TRIM22, FAS, SPATA18, SULF2, CDKN1A, GDF15, MYO6, CXCL5, CROT, EPPK1, ZMAT3 and CD44), with roles in the above-mentioned pathways, indicating that these cells have similar functional responses to doxorubicin relaying on the p53 control of apoptosis. Eight genes are shared by both drug stress signatures (in CAL51 and CALDOX cells) and CALDOX resistant cells (FAS, SULF2, CDKN1A, CXCL5, CD44, SPATA18, TRIM22 and CROT), many of them targets of p53. This corroborates experimental data indicating that CALDOX cells, even in the absence of drug, have activated, at least partially, the p53-p21 axis and DNA damage response. Although this eight-gene signature might be an indicator of adaptive resistance, as this transient phenomenon due to short-term stress may not revert to its original state upon withdrawal of the stressor, previous experimental data indicates that the p53-p21 axis is not responsible for doxorubicin resistance. Importantly, TOP2A is not responsive to doxorubicin treatment and thus absent in both drug stress signatures. This indicates that during the generation of doxorubicin resistance, cells acquire genetic changes likely to be random, leading to down regulation of TOP2A, but selected during the generation of cells due to the presence of drug in the culture medium. This poses a considerable constraint for the development of strategies aimed at avoiding the emergence of drug resistance in the clinic.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética
4.
J Enzyme Inhib Med Chem ; 38(1): 118-137, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36305290

RESUMO

A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02- to 8.66-fold more potent than doxorubicin against T-24 cancer cells. Ten compounds were 1.2- to 7.1-fold more potent than doxorubicin against PC-3 cancer cells. The most potent compounds 6, 7a, 7b, 8a, 9a, and 10c showed significant Topo II inhibitory activity (83-90% at 100 µM concentration). Compounds 6, 8a, and 10c were 1.01- to 2.32-fold more potent than doxorubicin. Compounds 6 and 8a induced apoptosis in T-24 (16.8- and 20.1-fold, respectively compared to control). This evidence was supported by an increase in the level of apoptotic caspase-3 (5.23- and 7.6-fold, sequentially). Both compounds arrested the cell cycle in the S phase in T-24 cancer cells while in PC-3 cancer cells the two compounds arrested the cell cycle in the G1 phase. Molecular docking simulations of compounds 6 and 8a into the Topo II active site rationalised their remarkable Topo II inhibitory activity.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo II , DNA Topoisomerases Tipo II/metabolismo , Ciprofloxacina/farmacologia , Ciprofloxacina/química , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Antineoplásicos/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células
5.
Mol Med Rep ; 27(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36382656

RESUMO

Colorectal cancer (CRC) is one of the deadliest malignant tumors worldwide and its prevalence is increasing in South Korea. The efficacy of combined treatment with natural product­derived and chemotherapy agents including curcumin combined with 5­fluorouracil, resveratrol combined with cisplatin and epigallocatechin­3­gallate (EGCG) combined with cisplatin in preventing cancer progression and killing cancer cells has emerged. The Akt and Hippo signaling pathways serve a key role in colorectal tumor growth; however, the exact role of the crosstalk between Akt and Hippo signaling pathways in CRC remains poorly elucidated. The combined effect of UA and DOX on the cell proliferation, apoptosis, migration and cell cycle of CRC cells were investigated by performing Cell proliferation assay, a soft agar colony formation assay, flow cytometry, wound healing assay and western blotting assay. Subsequently, the expression of AKT and Hippo signaling pathway­associated proteins were also assessed by western blot assay. Moreover, a xenograft nude mouse model was constructed to verify the effects of UA and DOX on the tumorigenesis of HCT116 cell in vivo. The present study reported that ursolic acid (UA) strongly enhanced the antitumor action of doxorubicin (DOX) via blocking the Akt/glycogen synthase kinase­3ß (Gsk3ß) signaling pathway and activating tumor­suppressive Hippo signaling (mammalian Ste20­like kinase 1 and 2, salvador family WW domain containing protein 1 and MOB kinase activator 1), thereby downregulating downstream effector yes­associated protein 1 (Yap) and connective tissue growth factor (CTGF) protein expression levels in CRC cells. Furthermore, The PI3K inhibitor LY294002 further suppressed Akt activity and enhance the function of Hippo pathway­associated proteins in DOX + UA treated cells; this effect led to subsequent oncogenic Yap and CTGF inhibition following combined treatment, whereas Akt activator SC79 exerted an opposite effect in CTGF expression. In vivo, treatment with UA combined with DOX markedly suppressed the progression of CRC without any toxic effects on a xenograft mouse model by disrupting Akt signaling and activating the Hippo signaling pathway. These results demonstrated that UA and DOX treatment successfully induced Akt/Gsk3ß inactivation via Hippo signaling pathway activation to promote Yap degradation, resulting in the inhibition of colorectal tumorigenesis. In conclusion, these findings suggested that combination therapy with UA and DOX may be more effective than DOX alone. UA may be a novel anticancer strategy and could be considered for investigation as a complementary chemotherapy agent in the future.


Assuntos
Neoplasias Colorretais , Fosfatidilinositol 3-Quinases , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Hippo , Cisplatino/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais , Carcinogênese , Proliferação de Células , Apoptose , Doxorrubicina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Mamíferos/metabolismo
6.
Sci Signal ; 15(758): eabn8017, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36318618

RESUMO

Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.


Assuntos
Ferroptose , Sobrecarga de Ferro , Camundongos , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , DNA Mitocondrial/metabolismo , Ácido Aminolevulínico/metabolismo , Doxorrubicina/farmacologia , Mitocôndrias/genética , Miócitos Cardíacos/metabolismo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Heme/metabolismo , Dacarbazina/metabolismo
7.
Eur J Histochem ; 66(4)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36373350

RESUMO

Heart failure (HF) is often complicated by renal dysfunction. Tolvaptan and valsartan are two well-known agents for the treatment of HF. However, the role of tolvaptan/valsartan combination on HF with renal dysfunction remains unclear. To establish a mice model with HF with renal dysfunction, mice were intraperitoneally injected with doxorubicin (Dox). Echocardiogram was applied to assess the left ventricular function. Additionally, serum aldosterone (ALD) and angiotensin II (Ang II) level in mice were determined by ELISA. Meanwhile, western blot assay was used to evaluate the expressions of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax) and cleaved caspase 3 in the heart and kidney tissues of mice. In this study, we found that compared to tolvaptan or valsartan alone treatment group, tolvaptan/valsartan combination obviously improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS), and reduced serum ALD and Ang II level in Dox-treated mice. Additionally, tolvaptan/valsartan combination significantly prevented the inflammation and fibrosis of heart and kidney tissues in Dox-treated mice. Meanwhile, tolvaptan/valsartan combination notably inhibited the myocardial and renal cell apoptosis in Dox-treated mice via upregulation of Bcl-2 and downregulation of Bax and cleaved caspase 3, compared to the single drug treatment. Collectively, tolvaptan/valsartan combination could improve cardiac and renal functions, as well as prevent the fibrosis, inflammation and apoptosis of heart and kidney tissues in Dox-treated mice. Taken together, combining tolvaptan with valsartan might be a promising approach to achieve enhanced therapeutic effect for treatment of HF with renal dysfunction.


Assuntos
Insuficiência Cardíaca , Nefropatias , Camundongos , Animais , Valsartana/farmacologia , Valsartana/uso terapêutico , Tolvaptan/uso terapêutico , Tolvaptan/farmacologia , Volume Sistólico , Caspase 3 , Função Ventricular Esquerda/fisiologia , Proteína X Associada a bcl-2 , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Doxorrubicina/efeitos adversos , Rim/metabolismo , Fibrose , Inflamação
8.
JCO Glob Oncol ; 8: e2200165, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36351213

RESUMO

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. The purpose of this study was to evaluate the clinical features, prognostic factors, and results of DLBCL that was treated in the cancer centers of the public health system in Chile and compare cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). PATIENTS AND METHODS: Patients age > 15 years who were treated in 18 cancer centers in the country between 2001 and 2017 were included. The Kaplan-Meier method was used to calculate overall survival (OS), and Cox proportional hazard regression modeling was used to evaluate the effect of the addition of rituximab to CHOP on OS. RESULTS: A total of 1,807 patients were evaluated. The median age at diagnosis was 62 (range, 15-95) years, with a female predominance (53%). Half of the patients were age ≥ 60 years. Serology for HIV infection was positive in 5% of cases (96 cases). International Prognostic Index scores were available for 90% of patients, of which 45% had low-risk, 25% low-intermediate-risk, 18% high-intermediate-risk, and 11% high-risk scores. CHOP was administered to 986 patients (55%; median follow-up, 13.2 years) and R-CHOP to 821 patients (45%; median follow-up, 8.4 years). R-CHOP was associated with superior OS compared with CHOP (5-year 66% v 48%, and 10-year 53% v 35%; P < .001). CONCLUSION: Rituximab improved the survival of patients with DLBCL diagnosed and treated in Chile. The benefit was sustained over time, with curative rates of > 50%. This intervention shows that the inclusion of this biological drug justified the expenses incurred by the Ministry of Health in the National Lymphoma Protocols in Chile.


Assuntos
Infecções por HIV , Linfoma Difuso de Grandes Células B , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Rituximab/uso terapêutico , Vincristina/uso terapêutico , Prednisona/efeitos adversos , Saúde Pública , Infecções por HIV/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Chile/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos
9.
Rinsho Ketsueki ; 63(10): 1409-1414, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36351648

RESUMO

A 54-year-old male patient, who presented with multiple lymphadenopathies, bilateral leg edema, and oscheohydrocele, was diagnosed with diffuse large B-cell lymphoma (DLBCL) stage IVB. His lymphadenopathies disappeared after six courses of R-CHOP therapy, which consist of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone); however, right hypopyon and partly remaining testicular soft tissue masses with fluorodeoxyglucose accumulation were observed. Lymphoma cell infiltration was observed in the aqueous humor of the right anterior chamber and testis, which indicates DLBCL progression. Hypopyon disappeared after the first course of intrathecal chemotherapy combined with R-HDMA therapy, which consists of rituximab and high-dose methotrexate/cytarabine, but recurred in the third course. The patient then underwent busulfan and thiotepa (BuTT) therapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) after four courses of R-HDMA therapy. Hypopyon promptly disappeared after BuTT therapy and no hypopyon recurrence was observed 9 months after auto-PBSCT. Therefore, BuTT therapy is effective for hypopyon associated with refractory DLBCL.


Assuntos
Linfadenopatia , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Transplante de Células-Tronco de Sangue Periférico , Masculino , Humanos , Pessoa de Meia-Idade , Tiotepa/uso terapêutico , Bussulfano , Rituximab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Transplante Autólogo , Linfoma não Hodgkin/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Vincristina/uso terapêutico , Doxorrubicina/uso terapêutico , Linfadenopatia/tratamento farmacológico
10.
J Math Biol ; 85(6-7): 65, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36352309

RESUMO

Doxorubicin is a chemotherapy widely used to treat several types of cancer, including triple-negative breast cancer. In this work, we use a Bayesian framework to rigorously assess the ability of ten different mathematical models to describe the dynamics of four TNBC cell lines (SUM-149PT, MDA-MB-231, MDA-MB-453, and MDA-MB-468) in response to treatment with doxorubicin at concentrations ranging from 10 to 2500 nM. Each cell line was plated and serially imaged via fluorescence microscopy for 30 days following 6, 12, or 24 h of in vitro drug exposure. We use the resulting data sets to estimate the parameters of the ten pharmacodynamic models using a Bayesian approach, which accounts for uncertainties in the models, parameters, and observational data. The ten candidate models describe the growth patterns and degree of response to doxorubicin for each cell line by incorporating exponential or logistic tumor growth, and distinct forms of cell death. Cell line and treatment specific model parameters are then estimated from the experimental data for each model. We analyze all competing models using the Bayesian Information Criterion (BIC), and the selection of the best model is made according to the model probabilities (BIC weights). We show that the best model among the candidate set of models depends on the TNBC cell line and the treatment scenario, though, in most cases, there is great uncertainty in choosing the best model. However, we show that the probability of being the best model can be increased by combining treatment data with the same total drug exposure. Our analysis points to the importance of considering multiple models, built on different biological assumptions, to capture the observed variations in tumor growth and treatment response.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Teorema de Bayes , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Proliferação de Células
11.
Nanotechnology ; 34(5)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36317264

RESUMO

A targeted drug delivery system was developed to accumulate specific drugs around tumor cells based on the redox, temperature, and enzyme synergistic responses of mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-NH2) and Doxorubicin (DOX) for tumor therapy were prepared and loaded into the pores of MSN- NH2 to obtain DOX@MSN(DM NPs). Hyaluronic acid (HA) was used as the backbone and disulfide bond was used as the linker arm to graft carboxylated poly (N-isopropylacrylamide)(PNIPAAm-COOH) to synthesize the macromolecular copolymer (HA-SS-PNIPAAm), which was modified to DM NPs with capped ends to obtain the nano-delivery system DOX@MSN@HA-SS-PNIPAAm(DMHSP NPs), and a control formulation was prepared in a similar way. DMHSP NPs specifically entered tumor cells via CD44 receptor-mediated endocytosis; the high GSH concentration (10 mM) of cells severed the disulfide bonds, the hyaluronidase sheared the capped HA to open the pores, and increased tumor microenvironment temperature due to immune response can trigger the release of encapsulated drugs in thermosensitive materials.In vitroandin vivoantitumor and hemolysis assays showed that DMHSP NPs can accurately target hepatocellular carcinoma cells with a good safety profile and have synergistic effects, which meant DMHSP NPs had great potential for tumor therapy.


Assuntos
Nanopartículas , Neoplasias , Humanos , Porosidade , Doxorrubicina/química , Dióxido de Silício/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Ácido Hialurônico/química , Dissulfetos , Portadores de Fármacos/química , Microambiente Tumoral
12.
Molecules ; 27(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36364051

RESUMO

One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to determine the ability of 2,4-DNP to sensitize prostate cancer cells with different metabolic phenotypes to the action of known anthracyclines (doxorubicin and epirubicin). The synergistic effect of the anthracyclines and 2,4-DNP was determined using an MTT assay, apoptosis detection and a cell cycle analysis. The present of oxidative stress in cancer cells was assessed by CellROX, the level of cellular thiols and DNA oxidative damage. The study revealed that the incubation of LNCaP prostate cancer cells (oxidative phenotype) with epirubicin and doxorubicin simultaneously with 2,4-DNP showed the presence of a synergistic effect for both the cytostatics. Moreover, it contributes to the increased induction of oxidative stress, which results in a reduced level of cellular thiols and an increased number of AP sites in the DNA. The synergistic activity may consist of an inhibition of ATP synthesis and the simultaneous production of toxic amounts of ROS, destroying the mitochondria. Additionally, the sensitivity of the LNCaP cell line to the anthracyclines is relatively higher compared to the other two (PC-3, DU-145).


Assuntos
Antraciclinas , Neoplasias da Próstata , Humanos , Masculino , Antraciclinas/farmacologia , 2,4-Dinitrofenol/farmacologia , Epirubicina/farmacologia , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Dinitrofenóis/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Compostos de Sulfidrila
13.
Molecules ; 27(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36364190

RESUMO

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The 'nootropic-like' activity could be related to diminished AChE and neuroinflammatory mediator levels.


Assuntos
Comprometimento Cognitivo Relacionado à Quimioterapia , Nootrópicos , Animais , Ratos , Simulação de Acoplamento Molecular , Nootrópicos/farmacologia , Levetiracetam/farmacologia , Acetilcolinesterase/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , NF-kappa B/farmacologia , Ciclo-Oxigenase 2 , Doenças Neuroinflamatórias , Dinoprostona , Doxorrubicina/efeitos adversos , Colinérgicos/farmacologia , Estresse Oxidativo
14.
Molecules ; 27(21)2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36364209

RESUMO

The activity of the P-glycoprotein (P-gp) transporter encoded by the ABCB1 gene confers resistance to anticancer drugs and contributes to cancer-related mortality and morbidity. Recent studies revealed the cytotoxic effects of the endogenous dipeptide carnosine. The current study aimed to investigate the role of carnosine as a potential inhibitor of P-gp activity. We used molecular docking and molecular dynamic simulations to study the possible binding and stability of carnosine-P-gp interactions compared with verapamil. In vitro assays using doxorubicin-resistant NCI/ADR-RES cells were established to test the effects of carnosine (10-300 µM) on P-gp activity by the rhodamine-123 efflux assay and its effect on cell viability and doxorubicin-induced cytotoxicity. Verapamil (10 µM) was used as a positive control. The results showed that carnosine binding depends mainly on hydrogen bonding with GLU875, GLN946, and ALA871, with a higher average Hbond than verapamil. Carnosine showed significant but weaker than verapamil-induced rhodamine-123 accumulation. Carnosine and verapamil similarly inhibited cell viability. However, verapamil showed a more significant potentiating effect on doxorubicin-induced cytotoxicity than a weaker effect of carnosine at 300 µM. These results suggest that carnosine inhibits P-gp activity and potentiates doxorubicin-induced cytotoxicity at higher concentrations. Carnosine might be a helpful lead compound in the fight against multidrug-resistant cancers.


Assuntos
Antineoplásicos , Carnosina , Resistência a Múltiplos Medicamentos , Carnosina/farmacologia , Carnosina/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos , Doxorrubicina/farmacologia , Rodamina 123/farmacologia , Verapamil/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia
15.
Molecules ; 27(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36364286

RESUMO

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug-loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin-loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanotubos de Carbono , Humanos , Feminino , Nanotubos de Carbono/química , Ligantes , Espectroscopia de Infravermelho com Transformada de Fourier , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Antineoplásicos/farmacologia , Antineoplásicos/química , Microambiente Tumoral
16.
Molecules ; 27(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36364379

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the betacoronavirus genus can cause severe respiratory illnesses, accompanied by pneumonia, multiorgan failure, and ultimately death. CoVs have the ability to transgress species barriers and spread swiftly into new host species, with human-to-human transmission causing epidemic diseases. Despite the severe public health threat of MERS-CoV, there are currently no vaccines or drugs available for its treatment. MERS-CoV papain-like protease (PLpro) is a key enzyme that plays an important role in its replication. In the present study, we evaluated the inhibitory activities of doxorubicin (DOX) against the recombinant MERS-CoV PLpro by employing protease inhibition assays. Hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of DOX showed an IC50 value of 1.67 µM at 30 min. Subsequently, we confirmed the interaction between DOX and MERS-CoV PLpro by thermal shift assay (TSA), and DOX increased ΔTm by ~20 °C, clearly indicating a coherent interaction between the MERS-CoV PL protease and DOX. The binding site of DOX on MERS-CoV PLpro was assessed using docking techniques and molecular dynamic (MD) simulations. DOX bound to the thumb region of the catalytic domain of the MERS-CoV PLpro. MD simulation results showed flexible BL2 loops, as well as other potential residues, such as R231, R233, and G276 of MERS-CoV PLpro. Development of drug repurposing is a remarkable opportunity to quickly examine the efficacy of different aspects of treating various diseases. Protease inhibitors have been found to be effective against MERS-CoV to date, and numerous candidates are currently undergoing clinical trials to prove this. Our effort follows a in similar direction.


Assuntos
Coronavírus da Síndrome Respiratória do Oriente Médio , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Papaína/química , Peptídeo Hidrolases/metabolismo , Reposicionamento de Medicamentos , Doxorrubicina/farmacologia , Doxorrubicina/metabolismo
17.
Drug Deliv ; 29(1): 3291-3303, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36352741

RESUMO

Osteosarcoma is a bone tumor with a high incidence in children and adolescents. Chemotherapy for osteosarcoma is limited, and effective targeted drugs are urgently needed to treat osteosarcoma. Exosomes as a natural nano drug delivery platform have been widely studied and proven to have good drug delivery performance. However, the low production of exosomes hinders its development as a carrier. Exosome mimetics (EMs) as an alternative product of exosomes solve the problem of low production of exosomes and maintain the good performance of exosomes as carriers. In this study, bone marrow mesenchymal stem cells (BMSCs) were sequentially extruded to generate EMs to encapsulate doxorubicin (EM-Dox) to treat osteosarcoma. The results showed that we successfully prepared EMs of BMSC, and EM-Dox was prepared using an active-loading approach. Our engineered EM-Dox demonstrated significantly more potent tumor inhibition activity and fewer side effects than free doxorubicin. This novel biological nanomedicine system provides a promising opportunity to develop novel precision medicine for osteosarcoma.


Assuntos
Neoplasias Ósseas , Exossomos , Células-Tronco Mesenquimais , Osteossarcoma , Criança , Humanos , Adolescente , Linhagem Celular Tumoral , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Doxorrubicina , Neoplasias Ósseas/tratamento farmacológico
18.
N Engl J Med ; 387(18): 1649-1660, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36322844

RESUMO

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).


Assuntos
Antineoplásicos Imunológicos , Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotin , Doença de Hodgkin , Adolescente , Adulto , Criança , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/efeitos adversos , Brentuximab Vedotin/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos
19.
Medicine (Baltimore) ; 101(44): e31326, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36343038

RESUMO

INTRODUCTION: Monomorphic intestinal T-cell lymphoma (MEITL) is a rare, aggressive peripheral T-cell lymphoma that arises from intestinal epithelial lymphocytes. Currently, MEITL lacks standard treatment options. Under the current treatment regimen, the median survival time for patients is only 7 months. Chemotherapy followed by hematopoietic stem cell transplantation may improve patient outcomes. New anti-lymphoma drugs, including chidamide and PEG-asparaginase, are being tested against MEITL. To our knowledge, there are currently no data on the pegylated liposomal doxorubicin (PLD) regimen for MEITL therapy.Patient concerns, diagnosis and interventions: We report the case of a 54-year-old patient diagnosed with MEITL who presented with abdominal pain and was treated with a cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide regimen containing PLD. OUTCOMES: After 15 months of follow-up, the patient is currently alive and disease free. The application of doxorubicin liposomes in chemotherapy regimens may be a new way to treat MEITL. REVIEW: We searched the literature on MEITL and selected 52 case reports. We summarized the clinical characteristics and treatment of 53 patients (including the current patient). CONCLUSION: It highlights 2 important clinical findings. First, for patients with MEITL treated with the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide regimen, PLD has fewer adverse reactions and better long-term survival than doxorubicin. Second, an early diagnosis is necessary for prompt treatment. We believe that this manuscript will be valuable to all the researchers who are interested in.


Assuntos
Linfoma de Células T Associado a Enteropatia , Linfoma de Células T Periférico , Humanos , Pessoa de Meia-Idade , Vincristina , Prednisona/uso terapêutico , Etoposídeo , Protocolos de Quimioterapia Combinada Antineoplásica , Doxorrubicina , Ciclofosfamida/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico
20.
Medicine (Baltimore) ; 101(44): e31631, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36343072

RESUMO

RATIONALE: Clear cell sarcoma of soft tissue (CCSST) is a rare malignant tumor that occurs in the extremities of young adults. CCSST has been documented to have atypical histopathological features, such as epidermotropism or myxoid differentiation, which may set pitfalls in the differential diagnosis. We report a case of CCSST with plasmacytoid morphology which has never been described. PATIENT CONCERNS: A 15-year-old male, presented with a 5-cm mass in his left inguinal area. DIAGNOSIS: Positron emission tomography-computed tomography examination showed nodules in the left groin and the lung, the latter was considered metastasis. A core needle biopsy with the diagnosis of CCSST with plasmacytoid morphology was made according to histology, immunostaining, and molecular analysis. INTERVENTIONS: The patient received chemotherapy of doxorubicin and ifosfamide. OUTCOMES: The patient failed to respond to the standard chemotherapy and deceased twelve months after diagnosis. LESSONS: This special case of CCSST with plasmacytoid features demonstrated a morphological variation never been documented and may easily lead to misdiagnosis. For such cases, molecular analysis is essential to provide solid evidence for accurate diagnosis.


Assuntos
Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Masculino , Adulto Jovem , Humanos , Adolescente , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Ifosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Extremidades/patologia
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