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1.
Autophagy ; : 1-17, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33315519

RESUMO

Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific Atg7 +/- heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated Plk1 knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity in vivo by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. Abbreviations: 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII.

2.
Toxicol Lett ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33248157

RESUMO

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.

3.
Cell Res ; 30(9): 779-793, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32296111

RESUMO

Hand-foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.

4.
Toxicol Appl Pharmacol ; 383: 114768, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31639374

RESUMO

Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process.


Assuntos
Apoptose/efeitos dos fármacos , Crizotinibe/toxicidade , Dano ao DNA/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dano ao DNA/fisiologia , Relação Dose-Resposta a Droga , Hepatócitos/patologia , Humanos , Masculino , Inibidores de Proteínas Quinases/toxicidade
5.
Sensors (Basel) ; 19(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823553

RESUMO

Ultra high frequency radio frequency identification (UHF RFID)-based indoor localization technology has been a competitive candidate for context-awareness services. Previous works mainly utilize a simplified Friis transmission equation for simulating/rectifying received signal strength indicator (RSSI) values, in which the directional radiation of tag antenna and reader antenna was not fully considered, leading to unfavorable performance degradation. Moreover, a k-nearest neighbor (kNN) algorithm is widely used in existing systems, whereas the selection of an appropriate k value remains a critical issue. To solve such problems, this paper presents an improved kNN-based indoor localization algorithm for a directional radiation scenario, IKULDAS. Based on the gain features of dipole antenna and patch antenna, a novel RSSI estimation model is first established. By introducing the inclination angle and rotation angle to characterize the antenna postures, the gains of tag antenna and reader antenna referring to direct path and reflection paths are re-expressed. Then, three strategies are proposed and embedded into typical kNN for improving the localization performance. In IKULDAS, the optimal single fixed rotation angle is introduced for filtering a superior measurement and an NJW-based algorithm is advised for extracting nearest-neighbor reference tags. Furthermore, a dynamic mapping mechanism is proposed to accelerate the tracking process. Simulation results show that IKULDAS achieves a higher positioning accuracy and lower time consumption compared to other typical algorithms.

6.
Eur J Pharmacol ; 847: 26-31, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30660576

RESUMO

Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 µM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/análogos & derivados , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Produtos Biológicos/farmacologia , Linhagem Celular , Curcumina/farmacologia , Diarileptanoides , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Obstrução Ureteral/tratamento farmacológico , Sistema Urinário/efeitos dos fármacos
7.
Toxicol Appl Pharmacol ; 366: 10-16, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653976

RESUMO

Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis.


Assuntos
Bleomicina , Citocinas/metabolismo , Fibroblastos/enzimologia , Pulmão/enzimologia , Macrófagos Alveolares/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Fibrose Pulmonar/enzimologia , Animais , Linhagem Celular , Movimento Celular , Técnicas de Cocultura , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Fibroblastos/patologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Camundongos Endogâmicos ICR , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais , Fatores de Tempo
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