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1.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444909

RESUMO

Glucosinolates (GLS) and their derivatives are secondary plant metabolites abundant in Brassicaceae. Due to the enzymatic reaction between GLS and myrosinase enzyme, characteristic compounds with a pungent taste are formed, used by plants to defend themselves against insect herbivores. These GLS derivatives have an important impact on human health, including anti-inflammation and anti-cancer effects. However, GLS derivatives' formation needs previous enzymatic reactions catalyzed by myrosinase enzyme. Many of the brassica-based foods are processed at a high temperature that inactivates enzymes, hindering its bioavailability. In the last decade, several studies showed that the human gut microbiome can provide myrosinase activity that potentially can raise the beneficial effects of consumption of vegetables rich in GLS. The variability of the human gut microbiome (HGM) in human populations and the diverse intake of GLS through the diet may lead to greater variability of the real dose of pro-healthy compounds absorbed by the human body. The exploitation of the genetic and biochemical potential of HGM and correct ecological studies of both isolated strains and mixed population are of great interest. This review focuses on the most recent advances in this field.


Assuntos
Brassica/química , Microbioma Gastrointestinal/fisiologia , Glucosinolatos/metabolismo , Anti-Inflamatórios/farmacocinética , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Manipulação de Alimentos , Glicosídeo Hidrolases/metabolismo , Temperatura Alta/efeitos adversos , Humanos , Paladar , Verduras/química
2.
ACS Appl Mater Interfaces ; 13(33): 39055-39065, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433248

RESUMO

Polymer photosensitizers (PPSs) with the distinctive properties of good light-harvesting capability, high photostability, and excellent tumor retention effects have aroused great research interest in photodynamic therapy (PDT). However, their potential translation into clinic was often constrained by the hypoxic nature of tumor microenvironment, the aggregation-caused reduced production of reactive oxygen species (ROS), and the tedious procedure of manufacture. As a powerful and versatile strategy, vacancy engineering possesses the unique capability to effectively improve the photogenerated electron efficiency of nanomaterials for high-performance O2 and ROS production. Herein, by introducing vacancy engineering into the design of PPSs for PDT for the first time, we synthesized a novel PPS of Au-decorated polythionine (PTh) nanoconstructs (PTh@Au NCs) with the unique integrated features of distinguished O2 self-evolving function and highly efficient ROS generation for achieving the greatly enhanced PDT efficacy toward hypoxic tumor both in vitro and in vivo. The incorporation of Au into PTh leads to the special PTh-Au heterostructure-induced sulfur vacancies in PTh@Au NCs, which results in an efficient electron-hole separation performance and also plays a key role in a long lifetime of free electrons and holes. Accordingly, an ∼2- to 3-fold ROS generation and an ∼1.5-fold increase of O2 self-supply than the pure PTh nanoparticles (NPs) were obtained even under hypoxic conditions upon exposure to 650 nm light. By combining such superior ROS generation and O2 self-supply performances with the outstanding cellular internalization and tumor accumulation capacities, an advanced antitumor effect with the achievement of almost complete hypoxic tumor elimination in vivo or 88% cell destruction in vitro was acquired by the PTh@Au NCs. In addition, the distinctive facile one-step redox strategy for PTh@Au NCs synthesis compared to the reported PPSs for PDT also makes it beneficial for potential practical application. The first introduction of vacancy engineering concept into PPSs in the field of PDT proposed in this work offers a new strategy for the development and design highly efficient PPSs for PDT applications.


Assuntos
Antineoplásicos/química , Ouro/química , Nanopartículas Metálicas/química , Fenotiazinas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Feminino , Humanos , Hipóxia/metabolismo , Camundongos , Neoplasias Experimentais , Oxigênio/metabolismo , Fenotiazinas/farmacocinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Polímeros/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica , Microambiente Tumoral
3.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
4.
ACS Appl Mater Interfaces ; 13(33): 39934-39948, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34396771

RESUMO

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Glutationa/química , Indóis/química , Nanopartículas/química , Oxaliplatina/química , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Glutationa/metabolismo , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos da radiação , Imunoterapia , Indóis/farmacocinética , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Oxaliplatina/farmacocinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Polietilenoglicóis/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
5.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361793

RESUMO

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.


Assuntos
Antineoplásicos/química , Química Click/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Radiossensibilizantes/química , Radioimunoterapia/métodos , Alcinos/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Azidas/química , Reação de Cicloadição/métodos , Ciclo-Octanos/química , Elétrons , Compostos Heterocíclicos com 1 Anel/química , Humanos , Concentração de Íons de Hidrogênio , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Neoplasias/química , Neoplasias/imunologia , Neoplasias/patologia , Fotoquimioterapia/métodos , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/farmacologia
6.
J Enzyme Inhib Med Chem ; 36(1): 1839-1859, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338119

RESUMO

A series of [1]benzothieno[2,3-c]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a-c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI50 of 4 nM-37 µM. Cytotoxicity of 5a-c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridinas/química , Piridinas/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Camundongos , Neoplasias da Próstata/patologia , Piridinas/síntese química , Piridinas/farmacocinética , Análise Espectral/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Enzyme Inhib Med Chem ; 36(1): 1760-1782, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340610

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC50 of 3.2 nM very close to positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC50 of 7.7 and 4.5 µM in comparison to sorafenib (IC50 = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular
8.
Expert Opin Drug Metab Toxicol ; 17(9): 1023-1030, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34275396

RESUMO

INTRODUCTION: The first-in-class BTK inhibitor ibrutinib has substantially changed the therapeutic landscape of chronic lymphocytic leukemia (CLL). The next-generation BTK inhibitor acalabrutinib is more selective and may have less off-target toxicities as compared to ibrutinib. Acalabrutinib has demonstrated safety and efficacy in CLL and has been approved to treat CLL. AREAS COVERED: Current clinical trials investigated acalabrutinib monotherapy or acalabrutinib-based combination therapies in relapsed/refractory and treatment-naive CLL. Data on the efficacy and safety of acalabrutinib in clinical trials were summarized in this review. The pharmacokinetic and pharmacodynamic data of acalabrutinib were also discussed. EXPERT OPINION: Acalabrutinib selectively inhibits BTK by covalent binding and shows rapid absorption and elimination. Acalabrutinib does not inhibit EGFR, TEC, or ITK and shows fewer off-target toxicities. Completed phase 3 trials have demonstrated that acalabrutinib improves the outcomes of patients with relapsed/refractory CLL and patients with treatment-naive CLL. The phase 3 trial that evaluates acalabrutinib versus ibrutinib has met its primary endpoint. Early phase studies suggested the combinations of acalabrutinib with a CD20 antibody and venetoclax led to high rates of undetectable minimal residual disease in the bone marrow in CLL patients and might provide a fixed-duration therapeutic option for patients with CLL.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/efeitos adversos , Pirazinas/farmacocinética
9.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299029

RESUMO

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer's disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.


Assuntos
Antineoplásicos/química , Química Farmacêutica , Curcumina/química , Compostos Radiofarmacêuticos/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Curcumina/administração & dosagem , Curcumina/farmacocinética , Humanos , Imagem Molecular , Distribuição Tecidual
10.
Expert Opin Drug Metab Toxicol ; 17(7): 803-821, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34278936

RESUMO

Introduction: Orally administered small molecule kinase inhibitors (KI) are a key class of targeted anti-cancer medicines that have contributed substantially to improved survival outcomes in patients with advanced disease. Since the introduction of KIs in 2001, there has been a building body of evidence that the benefit derived from these drugs may be further enhanced by individualizing dosing on the basis of concentration.Areas covered: This review considers the rationale for individualized KI dosing and the requirements for robust therapeutic drug monitoring (TDM). Current evidence supporting TDM-guided KI dosing is presented and critically evaluated, and finally potential approaches to address translational challenges for TDM-guided KI dosing and alternate approaches to support individualization of KI dosing are discussed.Expert opinion: Intuitively, the individualization of KI dosing through an approach such as TDM-guided dosing has great potential to enhance the effectiveness and tolerability of these drugs. However, based on current literature evidence it is unrealistic to propose that TDM-guided KI dosing should be routinely implemented into clinical practice.


Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética
11.
Toxicology ; 459: 152853, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252480

RESUMO

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Alcaloides de Berberina/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Gânglios Espinais/metabolismo , Mitocôndrias/metabolismo , Oxaliplatina/farmacocinética , Oxaliplatina/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Ratos , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo
12.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299320

RESUMO

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Neovascularização Patológica/induzido quimicamente , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Fluoruracila/metabolismo , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Talidomida/farmacologia , Timidina Fosforilase/genética , Regulação para Cima/efeitos dos fármacos
13.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209621

RESUMO

Silica nanoparticles (SiO2 NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto the SiO2 NPs surfaces. The DOX·HCl loading onto and release from the SiO2 NPs was monitored via UV-VIS and fluorescence spectra. Alternatively, the zeta potential was also used to monitor and evaluate the DOX·HCl loading process. The results showed that nearly 98% of DOX·HCl was effectively loaded onto the SiO2 NPs' surfaces by electrostatic interaction. The pH-dependence of the process wherein DOX·HCl release out of DOX·HCl-SiO2 NPs was investigated as well. For comparison, both the free DOX·HCl molecules and DOX·HCl-SiO2 NPs were used as the labels for cultured cancer cells. Confocal laser scanning microscopy images showed that the DOX·HCl-SiO2 NPs were better delivered to cancer cells which are more acidic than healthy cells. We propose that engineered DOX·HCl-SiO2 systems are good candidates for drug delivery and clinical applications.


Assuntos
Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Neoplasias , Dióxido de Silício , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Células MCF-7 , Microscopia Confocal , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
14.
J Enzyme Inhib Med Chem ; 36(1): 1732-1750, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34325596

RESUMO

There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 - 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 - 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Quinoxalinas/farmacocinética , Ratos , Relação Estrutura-Atividade
15.
Nat Commun ; 12(1): 4628, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330905

RESUMO

Simultaneous visualization of the relationship between multiple biomolecules and their ligands or small molecules at the nanometer scale in cells will enable greater understanding of how biological processes operate. We present here high-definition multiplex ion beam imaging (HD-MIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added structurally-unmodified small molecules. With this technology, the atomic constituents of the biomolecules themselves can be used in our system as the "tag" and we demonstrate measurements down to ~30 nm lateral resolution. We correlated the subcellular localization of the chemotherapy drug cisplatin simultaneously with five subnuclear structures. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. Unexpectedly, cells surviving multi-drug treatment with cisplatin and the BET inhibitor JQ1 demonstrated near total cisplatin exclusion from the nucleus, suggesting that selective subcellular drug relocalization may modulate resistance to this important chemotherapeutic treatment. Multiplexed high-resolution imaging techniques, such as HD-MIBI, will enable studies of biomolecules and drug distributions in biologically relevant subcellular microenvironments by visualizing the processes themselves in concert, rather than inferring mechanism through surrogate analyses.


Assuntos
Azepinas/metabolismo , Cisplatino/metabolismo , Espaço Intracelular/metabolismo , Espectrometria de Massa de Íon Secundário/métodos , Triazóis/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Azepinas/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cisplatino/farmacocinética , Citoplasma/metabolismo , Células HeLa , Humanos , Células Jurkat , Microscopia Confocal , Triazóis/farmacocinética
16.
Expert Rev Clin Pharmacol ; 14(9): 1173-1182, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181499

RESUMO

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.


Assuntos
Antineoplásicos/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Nefropatias/fisiopatologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Trióxido de Arsênio/efeitos adversos , Trióxido de Arsênio/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Testes de Função Renal , Síndrome do QT Longo/induzido quimicamente , Masculino , Metilação , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
17.
J Enzyme Inhib Med Chem ; 36(1): 1290-1312, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34187263

RESUMO

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/química , Pirimidinas/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
18.
J Med Chem ; 64(12): 8621-8643, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34060833

RESUMO

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
19.
J Med Chem ; 64(12): 8221-8245, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34105966

RESUMO

WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of the mixed lineage leukemia 1 (MLL1) complex. Dysregulation of the MLL1 gene is associated with human acute leukemias, and the direct disruption of the WDR5-MLL1 protein-protein interaction (PPI) is emerging as an alternative strategy for MLL-rearranged cancers. Here, we represent a new aniline pyrimidine scaffold for WDR5-MLL1 inhibitors. A comprehensive structure-activity analysis identified a potent inhibitor 63 (DDO-2213), with an IC50 of 29 nM in a competitive fluorescence polarization assay and a Kd value of 72.9 nM for the WDR5 protein. Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.


Assuntos
Antineoplásicos/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Compostos de Anilina/síntese química , Compostos de Anilina/metabolismo , Compostos de Anilina/farmacocinética , Compostos de Anilina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
20.
ACS Appl Mater Interfaces ; 13(25): 29340-29348, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34137582

RESUMO

We demonstrate a versatile nanoparticle with imaging-guided chemo-photothermal synergistic therapy and EpCAM-targeted delivery of liver tumor cells. EpCAM antibody (anti-EpCAM) and Pt(IV) were grafted onto the polydopamine carbon dots (PDA-CDs) by the amidation reaction. The EpCAM antibody of particles enables the targeted interaction with liver progenitor cells due to their overexpressed EpCAM protein. The tetravalent platinum prodrug [Pt(IV)] induces apoptosis with minimum toxic side effects through the interaction between cisplatin and tumor cell DNA. The nanoparticles displayed stable photothermal property and considerable anti-tumor therapeutic effect in vivo. Coupling with cellular imaging due to their fluorescence property, anti-EpCAM@PDA-CDs@Pt(IV) offers a convenient and effective platform for imaging-guided chemo-photothermal synergistic therapy toward liver cancers in the near future.


Assuntos
Antineoplásicos , Molécula de Adesão da Célula Epitelial/metabolismo , Corantes Fluorescentes , Indóis , Polímeros , Pontos Quânticos , Animais , Anticorpos Imobilizados/química , Anticorpos Imobilizados/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/farmacologia , Células HeLa , Células Hep G2 , Humanos , Indóis/química , Indóis/farmacocinética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Polímeros/química , Polímeros/farmacocinética , Pontos Quânticos/química , Pontos Quânticos/metabolismo , Nanomedicina Teranóstica/métodos
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