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1.
Metallomics ; 11(9): 1481-1489, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31348483

RESUMO

There is an ongoing need for the development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper(ii)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this work we performed a thorough study of the copper(ii)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce endoplasmic reticulum (ER) stress and subsequently cell death mediated by the unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper(ii)-phenanthroline complexes.


Assuntos
Antineoplásicos/farmacologia , Cobre/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Fenantrolinas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Fenantrolinas/química
2.
Drug Discov Today ; 24(4): 971-982, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30877077

RESUMO

The human respiratory system is continuously exposed to varying levels of hazardous substances ranging from environmental toxins to purposely administered drugs. If the noxious effects exceed the inherent regenerative capacity of the respiratory system, injured tissue undergoes complex remodeling that can significantly affect lung function and lead to various diseases. Advanced near-to-native in vitro lung models are required to understand the mechanisms involved in pulmonary damage and repair and to reliably test the toxicity of compounds to lung tissue. This review is an overview of the development of in vitro respiratory system models used for study of lung diseases. It includes discussion of using these models for environmental toxin assessment and pulmonary toxicity screening.


Assuntos
Modelos Biológicos , Sistema Respiratório , Animais , Técnicas de Cultura de Células , Humanos , Dispositivos Lab-On-A-Chip , Microfluídica , Sistema Respiratório/anatomia & histologia , Alicerces Teciduais
4.
Cell Tissue Res ; 374(3): 643-652, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30066106

RESUMO

Ovarian surface epithelium (OSE) forms a single layer of mostly cuboidal cells on surface of mammalian ovaries that is inherently exposed to cell stress evoked by tissue damage every ovulation and declines morphologically after menopause. Endoplasmic reticulum (ER) is a principal cell organelle involved in proteosynthesis, but also integrating various stress signals. ER stress evokes a conserved signaling pathway, the unfolded protein response (UPR), leading to cell death or adaptation to stress conditions. In this work, we document that mouse OSE suffers from ER stress during replicative senescence in vitro, develops abnormalities in ER and initiates UPR. Attenuation of ER stress in senescent OSE by tauroursodeoxycholic acid (TUDCA) reconditions ER architecture and leads to delayed onset of senescence. In summary, we show for the first time a mutual molecular link between ER stress response and replicative senescence leading to phenotypic changes of non-malignant ovarian surface epithelium.


Assuntos
Senescência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Epitélio/patologia , Ovário/patologia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Regulação para Baixo/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Epitélio/ultraestrutura , Feminino , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Encurtamento do Telômero/efeitos dos fármacos , Tunicamicina/farmacologia , Regulação para Cima/efeitos dos fármacos
5.
Blood ; 131(11): 1206-1218, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29317454

RESUMO

Casein kinase 1δ/ε (CK1δ/ε) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.


Assuntos
Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Animais , Caseína Quinase 1 épsilon/genética , Caseína Quinase 1 épsilon/metabolismo , Caseína Quinase Idelta/genética , Caseína Quinase Idelta/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Piperidinas
6.
Cell Mol Life Sci ; 75(5): 849-857, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28929175

RESUMO

Two decades ago, following a systematic screening of LOH regions on chromosome 8p22, TUSC3 has been identified as a candidate tumor suppressor gene in ovarian, prostate and pancreatic cancers. Since then, a growing body of evidence documented its clinical importance in various other types of cancers, and first initial insights into its molecular function and phenotypic effects have been gained, though the precise role of TUSC3 in different cancers remains unclear. As a part of the oligosaccharyltransferase complex, TUSC3 localizes to the endoplasmic reticulum and functions in final steps of N-glycosylation of proteins, while its loss evokes the unfolded protein response. We are still trying to figure out how this mechanistic function is reconcilable with its varied effects on cancer promotion. In this review, we focus on cancer-related effects of TUSC3 and envisage a possible role of TUSC3 beyond endoplasmic reticulum.


Assuntos
Carcinogênese/genética , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Neoplasias/genética , Proteínas Supressoras de Tumor/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cromossomos Humanos Par 8 , Epigênese Genética , Loci Gênicos , Glicosilação , Humanos , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade de Órgãos , Proteínas Supressoras de Tumor/metabolismo , Resposta a Proteínas não Dobradas
7.
Mol Cancer Ther ; 16(9): 1831-1842, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28619751

RESUMO

Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Remoção de Radical Alquila/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Metilação , Camundongos , Estrutura Molecular , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Nanomedicine ; 12: 2265-2278, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28392686

RESUMO

Due to many adverse effects of conventional chemotherapy, novel methods of targeting drugs to cancer cells are being investigated. Nanosize carriers are a suitable platform for this specific delivery. Herein, we evaluated the long-term stability of the naturally found protein nanocarrier apoferritin (Apo) with encapsulated doxorubicin (Dox). The encapsulation was performed using Apo's ability to disassemble reversibly into its subunits at low pH (2.7) and reassemble in neutral pH (7.2), physically entrapping drug molecules in its cavity (creating ApoDox). In this study, ApoDox was prepared in water and phosphate-buffered saline and stored for 12 weeks in various conditions (-20°C, 4°C, 20°C, and 37°C in dark, and 4°C and 20°C under ambient light). During storage, a very low amount of prematurely released drug molecules were detected (maximum of 7.5% for ApoDox prepared in PBS and 4.4% for ApoDox prepared in water). Fourier-transform infrared spectra revealed no significant differences in any of the samples after storage. Most of the ApoDox prepared in phosphate-buffered saline and ApoDox prepared in water and stored at -20°C formed very large aggregates (up to 487% of original size). Only ApoDox prepared in water and stored at 4°C showed no significant increase in size or shape. Although this storage caused slower internalization to LNCaP prostate cancer cells, ApoDox (2.5 µM of Dox) still retained its ability to inhibit completely the growth of 1.5×104 LNCaP cells after 72 hours. ApoDox stored at 20°C and 37°C in water was not able to deliver Dox inside the nucleus, and thus did not inhibit the growth of the LNCaP cells. Overall, our study demonstrates that ApoDox has very good stability over the course of 12 weeks when stored properly (at 4°C), and is thus suitable for use as a nanocarrier in the specific delivery of anticancer drugs to patients.


Assuntos
Apoferritinas/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoferritinas/administração & dosagem , Apoferritinas/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/química , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Água/química
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