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1.
Anticancer Res ; 39(9): 4775-4779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519578

RESUMO

BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Osteossarcoma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Nanomedicine ; 14: 4975-4989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371942

RESUMO

The porous surface of a polyetheretherketone (PK)-nanoporous lithium-doped magnesium silicate (NLS) blend (PKNLS) was fabricated on a PK surface by layer-by-layer pressuring, sintering, and salt-leaching. As controls, porous surfaces of a PK/lithium-doped magnesium silicate blend (PKLS) and PK were fabricated using the same method. The results revealed that porosity, water absorption, and protein absorption of the porous surface of PKNLS containing macropores and nanopores were obviously enhanced compared to PKLS and PK containing macropores without nanopores. In addition, PKNLS, with both macroporostiy and nanoporosity, displayed the highest ability of apatite mineralization in simulated body liquid, indicating excellent bioactivity. In vitro responses (including adhesion, proliferation, and differentiation) of MC3T3E1 cells to PKNLS were significantly enhanced compared to PKLS and PK. In vivo implantation results showed that new bone grew into the macroporous surface of PKNLS, and the amount of new bone for PKNLS was the highest. In short, PKNLS integration with PK significantly promoted cells/bone-tissue responses and exhibited excellent osteogenesis in vivo, which might have great potential for bone repair.


Assuntos
Osso e Ossos/fisiologia , Cetonas/farmacologia , Lítio/farmacologia , Silicatos de Magnésio/farmacologia , Nanoporos , Osteoblastos/citologia , Polietilenoglicóis/farmacologia , Adsorção , Fosfatase Alcalina/metabolismo , Animais , Apatitas/química , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imagem Tridimensional , Masculino , Camundongos , Nanoporos/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Osteogênese/efeitos dos fármacos , Porosidade , Coelhos , Água/química , Difração de Raios X
3.
J Sci Food Agric ; 99(14): 6267-6277, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31259414

RESUMO

BACKGROUND: 2-Heptanone is a volatile liquid known to be effective in protecting honey bees from parasitic mite infestations in hives. The present study aimed to show that chemical derivatives of 2-heptanone would release the ketone for a significantly longer time than it takes for the pure ketone to evaporate and preferably for as long as two brood cycles of a honey bee (42 days). RESULTS: A liquid ketal of 2-heptanone with glycerol (Glyc-Ket) and solid ketals of the ketone with polyvinyl alcohol (PVAl-Ket), containing different amounts of the ketone, were synthesized. The fully resolved 1 H and 13 C nuclear magenetic resonance (NMR) spectra of the ketals are discussed. In the case of the polymer, differential scanning calorimetry (DSC) of a ketal was also compared with the unketalized polyvinyl alcohol. The length of time for which 2-heptanone was released by the ketals was determined by gas chromatography-mass spectrometry of the headspace. In the case of Glyc-Ket, the concentration of the 2-heptanone in the liquid phase was also monitored by 1 H NMR spectroscopy. The deketalization was pH dependent, ranging between 2.0 and 2.5 for Glyc-Ket and between 2.0 and 3.5 for PVAl-Ket. CONCLUSION: Under bee hive conditions, the release of 55 mmol 2-heptanone from Glyc-Ket lasted for 42 days, whereas the release of the ketone from the PVAl-Ket with a similar amount of the ketone lasted for 23 days, versus a maximum of 17 days for an equivalent amount of the pure ketone. These ketals therefore have the potential to be effective mite repellants for the protection of honey bees. © 2019 Society of Chemical Industry.


Assuntos
Abelhas/fisiologia , Repelentes de Insetos/farmacologia , Cetonas/farmacologia , Ácaros/efeitos dos fármacos , Animais , Ácaros/crescimento & desenvolvimento
4.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
5.
Expert Opin Drug Saf ; 18(5): 347-355, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31107111

RESUMO

Introduction: Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens. Areas covered: This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC. Expert opinion: As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Furanos/efeitos adversos , Cetonas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Feminino , Furanos/administração & dosagem , Furanos/farmacologia , Humanos , Cetonas/administração & dosagem , Cetonas/farmacologia , Metástase Neoplásica , Taxa de Sobrevida
6.
J Med Life ; 12(1): 5-9, 2019 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31123518

RESUMO

This study is aimed to review the applications of Polyether Ether Ketone (PEEK) in dentistry. The increased demand for aesthetics, legislation in some developed countries, few drawbacks with existing materials and clinicians shifting their paradigms towards metal free restorations led space for the metal-free restorations in today's dental practice. An electronic literature search was conducted through Medline via PubMed, Wiley Online library, EBSCOhost, Science Direct, as well as the Google Scholar between January 2010 and March 2018 using the keywords: PEEK, modified PEEK, PEEK and Dental, advantages of PEEK, applications of PEEK in dentistry and PEEK Implants. A total of 103 articles were found in the literature search and out of these, 18 were not related to our study and hence were excluded. Finally, 85 articles were found to be relevant. PEEK has been explained for a number of applications in dental practice. The literature showed that the PEEK material has superior mechanical properties with different uses in various specialties of dentistry.


Assuntos
Odontologia , Cetonas/farmacologia , Polietilenoglicóis/farmacologia , Implantes Dentários , Humanos
7.
Cancer Sci ; 110(7): 2247-2257, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31099446

RESUMO

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Furanos/administração & dosagem , Glioblastoma/tratamento farmacológico , Cetonas/administração & dosagem , Regiões Promotoras Genéticas/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Feminino , Furanos/farmacologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Humanos , Injeções Intraperitoneais , Cetonas/farmacologia , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Telomerase/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mater Sci Eng C Mater Biol Appl ; 101: 232-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029316

RESUMO

Polyetheretherketone (PEEK) has been used in orthopedic surgery for several decades. Numerous methods were invented to alter the properties of PEEK. By adding nanoparticles, fibers, etc., elastic modulus and strength of PEEK can be changed to meet certain demand. In this study, tantalum (Ta), a promising metal, was introduced to modify the properties of PEEK, in which PEEK was reinforced with different contents of tantalum nanoparticles (from 1 wt% to 9 wt%). Mechanical properties and biological functions (both in vitro and in vivo) were then investigated. The highest elastic modulus and compressive strength were observed in 3%Ta-PEEK. Cell experiments as cell adhesion, collagen secretion, biomineralization and osteogenesis related gene expression showed preferable results in 3%Ta-PEEK and 5%Ta-PEEK. Improved bone integration was shown in 3%Ta-PEEK and 5%Ta-PEEK in vivo. Above all, enhanced mechanical properties and promoted bone formation were proved for 3%Ta-PEEK and 5%Ta-PEEK compared to others groups both in vitro and in vivo, suggesting that the addition of tantalum nanoparticles modified the osseointegration ability of PEEK. This composite of tantalum and PEEK could have a clinical potential for orthopedic implants.


Assuntos
Cetonas/farmacologia , Nanopartículas/química , Osteogênese/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Tantálio/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Varredura Diferencial de Calorimetria , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Colágeno/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Teste de Materiais , Camundongos , Minerais/metabolismo , Nanopartículas/toxicidade , Osseointegração/efeitos dos fármacos , Osteogênese/genética , Ratos Sprague-Dawley , Espectrometria por Raios X , Propriedades de Superfície , Termogravimetria
9.
Eur J Med Chem ; 171: 180-194, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30921758

RESUMO

Thiosemicarbazones (TSC) are a subclass of iron-chelating agents that are believed to have an anticancer activity. The high potential for the application of this compound class can be illustrated by a fact that three TSC have entered clinical trials. The ability to chelate metal ions results in several biochemical changes in the cellular metabolism and growth. An important factor that determines the antitumor activity of TSC is a level of iron regulatory proteins and the antioxidant potential that is specific for each type of cancer cell. However, despite the increasing interest in TSC, their mechanism of anticancer activity is still unclear. For a more effective and rational design, it is crucial to determine and describe the abovementioned issues. In this report, we describe a series of new TSC that are designed on the four main structural scaffolds. The anticancer activity of these compounds was evaluated against a panel of cancer cell lines including colon and breast cancers and gliomas. Special attention was paid to the metal-dependent proteins. The impact of the tested TSC on the cell cycle and redox homeostasis was also determined. These results confirm a p53-independent mechanism of apoptosis.


Assuntos
Antineoplásicos/farmacologia , Cetonas/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/química , Estrutura Molecular , Piridinas/química , Quinolinas/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química
10.
Bull Environ Contam Toxicol ; 102(6): 880-886, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923837

RESUMO

Fungicidal effect of 2-amino-4-nitrophenol and its derivates, prepared by replacing the hydrogen atom in its amino group by different organic radicals was studied. Evaluation of the biological activity of studied substances by сomputational chemistry methods was performed. Toxicity of 2-amino-4-nitrophenol and synthesized N-(2-hydroxy-5-nitrophenyl)formamide and N-(2-hydroxy-5-nitrophenyl)acetamide to six species of phytophatogen fungi were tested in the experiment. The results of the study demonstrate that replacement of the hydrogen atom in the amino group by a aldehyde group leads to an increase in fungicidal activity with respect to Rhizoctonia solani and Bipolaris sorokiniana. A replacement of the hydrogen atom by a ketone group increases the inhibitory effect on Sclerotinia sclerotiorum and Venturia inaequalis. The paper contains comparative data on the fungicide effect of commercial preparation for studied fungi also.


Assuntos
Ascomicetos/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Nitrofenóis/farmacologia , Rhizoctonia/efeitos dos fármacos , Acetamidas/química , Acetamidas/farmacologia , Formamidas/química , Formamidas/farmacologia , Fungicidas Industriais/química , Cetonas/química , Cetonas/farmacologia , Nitrofenóis/química , Relação Estrutura-Atividade
11.
Biol Pharm Bull ; 42(5): 814-818, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30787205

RESUMO

In addition to their major targets, clinically effective drugs may have unknown off-targets. By identifying such off-targets it may be possible to repurpose approved drugs for new indications. We are interested in the Golgi apparatus as a novel target for cancer therapy, but there is a paucity of candidate Golgi-disrupting drugs. Here, we aimed to identify Golgi-disrupting compounds from a panel of 34 approved anticancer drugs by using HBC-4 human breast cancer cells and immunofluorescence microscopy to visualize the Golgi apparatus. The screen identified five drugs having Golgi-disrupting activity. Four of them were vinca alkaloids (vinorelbine, vindesine, vincristine and vinblastine), and the fifth drug was eribulin. This is the first study to demonstrate that vinorelbine, vindesine and eribulin possess Golgi-disrupting activity. The 5 drugs are known to inhibit tubulin polymerization and to induce microtubule depolymerization. Interestingly, a microtubule-stabilizer paclitaxel did not induce Golgi-disruption, suggesting that the three-dimensionally preserved microtubules are partly responsible for maintaining the Golgi complex. Concerning eribulin, a noteworthy drug because of its high clinical efficacy against advanced breast cancer, we further confirmed its Golgi-disrupting activity in 3 different human breast cancer cell lines, BSY-1, MDA-MB-231 and MCF-7. Golgi-disruption may contribute to anticancer efficacy of eribulin. In conclusion, the present study revealed that 4 vinca alkaloids and eribulin possessed potential Golgi-disrupting activity among a panel of 34 approved anticancer drugs. Other drugs covering various molecular-targeted drugs and classical DNA-damaging drugs showed no Golgi-disrupting effect. These results suggest that tubulin polymerization-inhibitors might be promising candidate drugs with Golgi-disrupting activity.


Assuntos
Antineoplásicos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Furanos/farmacologia , Complexo de Golgi/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Cetonas/farmacologia , Células MCF-7 , Microtúbulos/efeitos dos fármacos , Paclitaxel/farmacologia , Vimblastina/farmacologia , Vincristina/farmacologia , Vindesina/farmacologia , Vinorelbina/farmacologia
12.
Eur J Med Chem ; 166: 90-107, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685536

RESUMO

Multitarget cannabinoids could be a promising therapeutic strategic to fight against Alzheimer's disease. In this sense, our group has developed a new family of indazolylketones with multitarget profile including cannabinoids, cholinesterase and BACE-1 activity. A medicinal chemistry program that includes computational design, synthesis and in vitro and cellular evaluation has allowed to us to achieve lead compounds. In this work, the synthesis and evaluation of a new class of indazolylketones have been performed. Pharmacological evaluation includes functional activity for cannabinoid receptors on isolated tissue. In addition, in vitro inhibitory assays in AChE/BuChE enzymes and BACE-1 have been carried out. Furthermore, studies of neuroprotective effects in human neuroblastoma SH-SY5Y cells and studies of the mechanisms of survival/death in lymphoblasts of patients with Alzheimer's disease have been achieved. The results of pharmacological tests have revealed that some of these derivatives (5, 6) behave as CB2 cannabinoid agonists and simultaneously show BuChE and/or BACE-1 inhibition.


Assuntos
Canabinoides/química , Canabinoides/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Indazóis/química , Cetonas/química , Cetonas/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Canabinoides/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Desenho de Drogas , Humanos , Cetonas/síntese química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Receptor CB2 de Canabinoide/antagonistas & inibidores
13.
Microbiol Res ; 219: 49-55, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30642466

RESUMO

Volatile organic compounds (VOCs) released from bacterial species have been reported as plant growth inducers. In this sense, Lactuca sativa was used as model vegetable to prospect the effects of 2-nonanone released by Bacillus sp. BCT9 at cellular and organ structure level, so we present preliminary results about the physiological effects. In this study, 2-day-old L. sativa were exposed to 2-nonanone for 10 days under two delivery systems: 1) 2-nonanone (abrupt delivery) and 2) 2-nonanone + lanolin (controlled delivery). The X-ray elemental microanalysis, scanning electron and confocal laser microscopies techniques were used to evaluate physiological changes "in vivo" conditions. The results indicated that 2-nonanone increased root and shoot length independently of 2-nonanone delivery system after 7 days of exposition. Additionally, 2-nonanone elicited the increase of anthocyanin and not affects chlorophyll content and electrolyte leakage percentage. The abrupt delivery elicited the increase of both length and density of root hair without causing changes in size of cell epidermis, while controlled delivery induced stomatal opening. Besides, 2-nonanone exposition did not modify the composition and distribution of carbon, nitrogen, phosphorus, potassium, and chlorine in the surface of plant tissue. The results suggested that 2-nonanone acts as a bacterial signal molecule to elicit changes related to root development without damaging the external morphology while epidermal cells at leaf level are not affected, suggesting that 2-nonanone can be an important tool to apply to vegetables.


Assuntos
Bacillus/metabolismo , Cetonas/farmacologia , Alface/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimento , Brotos de Planta/crescimento & desenvolvimento , Plântula/crescimento & desenvolvimento , Antocianinas/biossíntese , Clorofila/metabolismo , Células Epidérmicas/efeitos dos fármacos , Lanolina/farmacologia , Alface/microbiologia , Microscopia Confocal , Microscopia Eletrônica de Varredura , Folhas de Planta/metabolismo , Compostos Orgânicos Voláteis/metabolismo
14.
Eur J Med Chem ; 164: 602-614, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639896

RESUMO

The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.


Assuntos
Compostos Heterocíclicos/farmacologia , Cetonas/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteassoma/química , Animais , Antineoplásicos/química , Sítios de Ligação , Compostos Heterocíclicos/química , Xenoenxertos , Humanos , Cetonas/química , Modelos Moleculares , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo
15.
Pest Manag Sci ; 75(7): 2034-2042, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30624018

RESUMO

BACKGROUND: Diamondback moth Plutella xylostella (L.) (Lepidoptera: Plutellidae) is one of the most important crucifer pests. Commercial sex attractants have been developed to monitor and control P. xylostella. However, some studies have demonstrated a variety of pheromone responses of P. xylostella in different locations of the world. Soluble pheromone-binding proteins (PBPs), as a subfamily of odorant-binding proteins (OBPs), could selectively bind and transport pheromones across aqueous sensillar lymph to the surface of olfactory receptor neurons. It is worthy to study whether the mutation of PxylPBPs is one of the reasons for the different responses of sex attractors in different regions. RESULTS: In this study, P. xylostella males were collected from seven Chinese provinces, including Hainan, Guangdong, Yunnan, Fujian, Hunan, Zhejiang, and Hebei. PxylPBP1, PxylPBP2, and PxylPBP3 were cloned, and 3, 6, and 32 types of mutation pattern were identified, respectively. These mutation patterns were distributed in each province with different frequency. The results of fluorescence displacement binding assay and in silico simulation revealed that the three mutant PxylPBP3 were more sensitive to Z11-16:Ald than the reference protein (ACI28451). CONCLUSION: This result implied that mutation of PxylPBP3 may have contributed to regional differences in pheromone responses of P. xylostella. © 2019 Society of Chemical Industry.


Assuntos
Mariposas/genética , Mutação , Receptores Odorantes/genética , Atrativos Sexuais/farmacologia , Animais , China , Simulação por Computador , Geografia , Cetonas/farmacologia , Masculino , Simulação de Acoplamento Molecular , Mariposas/efeitos dos fármacos , Receptores Odorantes/química , Espectrometria de Fluorescência
16.
Cancer Sci ; 110(2): 751-760, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548479

RESUMO

Therapy based on targeted inhibition of BCR-ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)-positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR-ABL. We previously reported that a medium-chain fatty-acid derivative AIC-47 induced transcriptional suppression of BCR-ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph-positive leukemia cells. Herein, we showed that AIC-47 had anti-leukemic effects in either wild type (WT)- or mutated-BCR-ABL-harboring cells. AIC-47 suppressed transcription of BCR-ABL gene regardless of the mutation through downregulation of transcriptional activator, c-Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti-cancer drugs; however, we found that a point mutation of BCR-ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I-mutated cells, AIC-47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC-47 disrupted the Warburg effect. In a leukemic mouse model, AIC-47 greatly suppressed the increase in BCR-ABL mRNA level and improved hepatosplenomegaly regardless of the BCR-ABL mutation. Notably, the improvement of splenomegaly by AIC-47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC-47 might be a promising agent for overcoming the resistance of Ph-positive leukemia to therapy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/farmacologia , Proteínas de Fusão bcr-abl/genética , Compostos Heterocíclicos com 1 Anel/farmacologia , Cetonas/farmacologia , Leucemia/tratamento farmacológico , Mutação Puntual/genética , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
17.
Pest Manag Sci ; 75(1): 152-159, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29797492

RESUMO

BACKGROUND: The expression of P450 genes in insects can be induced by plant allelochemicals. To understand the induction mechanisms, we measured the expression profiles of three P450 genes and their promoter activities under the induction of plant allelochemicals. RESULTS: The inducible expression of CYP6CY19 was the highest among three genes, followed by those of CYP6CY22 and CYP6DA1. The regions from -687 to +586 bp of CYP6DA1, from -666 to +140 bp of CYP6CY19 and from -530 to +218 bp of CYP6CY22 were essential for basal transcriptional activity. The cis-elements for plant allelochemicals induction were identified between -193 and +56 bp of CYP6DA1, between -157 and +140 bp of CYP6CY19 and between -108 and +218 bp of CYP6CY22. These promoter regions were found to contain a potential aryl hydrocarbon receptor element binding site with a conservative sequence motif 5'-C/TAC/ANCA/CA-3'. All these four plant allelochemicals were able to induce the expression of these P450 genes. Tannic acid had a better inductive effect than other three plant allelochemicals. CONCLUSIONS: Our study identified the plant allelochemical responsive cis-elements. This provides further research targets aimed at understanding the regulatory mechanisms of P450 genes expression and their interactions with plant allelochemicals in insect pests. © 2018 Society of Chemical Industry.


Assuntos
Afídeos/efeitos dos fármacos , Afídeos/genética , Família 6 do Citocromo P450/genética , Proteínas de Insetos/genética , Feromônios/farmacologia , Animais , Afídeos/metabolismo , Família 6 do Citocromo P450/metabolismo , Gossipol/farmacologia , Proteínas de Insetos/metabolismo , Cetonas/farmacologia , Regiões Promotoras Genéticas , Quercetina/farmacologia , Taninos/farmacologia
18.
Anticancer Res ; 38(9): 5101-5108, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194155

RESUMO

BACKGROUND/AIM: The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs. MATERIALS AND METHODS: Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells. RESULTS: First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G2 arrest, and up-regulated expression of the DNA damage protein, pH2AX, when co-treated with HAL. Moreover, G2 phase arrest and apoptosis in HAL-ARI co-treated cells resulted from the up-regulation of retinoblastoma protein, reduced extracellular signal-regulated kinase pathway activity, and down-regulation of cell division cyclin protein. CONCLUSION: Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose.


Assuntos
Antimitóticos/farmacologia , Aripiprazol/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Regulação para Baixo , Sinergismo Farmacológico , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cetonas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Vincristina/farmacologia
19.
Anticancer Res ; 38(9): 5149-5157, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194162

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. MATERIALS AND METHODS: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. RESULTS: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. CONCLUSION: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.


Assuntos
Antimitóticos/farmacologia , Carcinoma de Células Escamosas/genética , Indanos/farmacologia , Neoplasias Bucais/genética , Piperidinas/farmacologia , Citrato de Sildenafila/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Donepezila , Regulação para Baixo , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cetonas/farmacologia , Neoplasias Bucais/tratamento farmacológico , Vincristina/farmacologia
20.
Eur J Med Chem ; 157: 1395-1405, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30196062

RESUMO

Chalcone, a natural structure, demonstrates many pharmacological activities including anticancer, and one promising mechanism is to modulate the generation of ROS. It has been known that pyroptosis is associated with anticancer effects, whereas there is fewer researches about ROS-mediated pyroptosis triggered by chemotherapy drugs. Moreover, incorporation of a α,ß-unsaturated ketone unit into chalcone may be an effective strategy for development of chemotherapy drugs. Hence, a number of chalcone analogues bearing a α,ß-unsaturated ketone were synthesized from chalcone analogues 1 with modest anticancer activities as the lead compound. Structure-activity relationship (SAR) studies confirmed the function of α,ß-unsaturated ketone to improve anticancer activity. Notably, compound 8, bearing a α,ß-unsaturated ketone, is the most potent inhibitor of cancer, with IC50 values on NCI-H460, A549 and H1975 cells of 2.3 ±â€¯0.3, 3.2 ±â€¯0.0 and 5.7 ±â€¯1.4 µM, respectively. Besides, 8 showed antiproliferative ability against NCI-H460 cells in a time- and concentration-dependent manner through modulating ROS to induce caspase-3-mediated pyroptosis, and displayed a better safety profile in vivo. Overall, these results demonstrated that compound 8 is a candidate agent and a potential lead compound for development of chemotherapy drugs, and can be used as a probe to further examine the mechanism of ROS-dependent pyroptosis.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Desenho de Drogas , Cetonas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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