Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Expert Rev Clin Pharmacol ; : 1-12, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33618586

RESUMO

Introduction: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.Areas covered: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.Expert opinion: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.

2.
Biochem Pharmacol ; 185: 114407, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33421376

RESUMO

The tumor suppressor protein p53 participates in the control of key biological functions such as cell death, metabolic homeostasis and immune function, which are closely related to various diseases such as tumors, metabolic disorders, infection and neurodegeneration. The p53 gene is also mutated in approximately 50% of human cancer cells. Mutant p53 proteins escape from the ubiquitination-dependent degradation, gain oncogenic function and promote the carcinogenesis, malignant progression, metastasis and chemoresistance. Therefore, the stability of both wild type and mutant p53 needs to be precisely regulated to maintain normal functions and targeting the p53 stability is one of the therapeutic strategies against cancer. Here, we focus on compound-induced degradation of p53 by both the ubiquitination-dependent proteasome and autophagy-lysosome degradation pathways. We also review other posttranslational modifications which control the stability of p53 and the biological functions involved in these processes. This review provides the current theoretical basis for the regulation of p53 abundance and its possible applications in different diseases.

3.
Expert Opin Drug Saf ; : 1-14, 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33356646

RESUMO

Introduction: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians. Areas covered: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms. Expert opinion: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.

4.
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.

5.
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.

6.
Expert Rev Clin Pharmacol ; 13(10): 1085-1093, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32896175

RESUMO

INTRODUCTION: The outbreak of COVID-19 caused by SARS-CoV-2 infection has become a serious hazard to global health. Apart from attacking respiratory system, it can induce multiorgan dysfunction, including cardiovascular system, liver, kidney, gastrointestinal, nervous system, and immune system. However, there are few reviews focusing on summary and comparison of diagnostic methods and complications induced by SARS-CoV-2 infection, which places a significant limit on the effective management. AREAS COVERED: This review is a blend of evidence obtained by literature retrieval from PubMed, clinical experience, and the authors' opinions. We searched PubMed using the terms 'COVID-19 & diagnosis' and 'COVID-19 & complications' and selected the most relevant articles. Here we summarize the diagnostic methods that are available in clinic and discuss their different characters. Furthermore, the review offers an insight into the symptoms, incidence, and clinical strategies of complications associated with SARS-CoV-2 infection. EXPERT OPINION: COVID-19 has been a global pandemic, which requires rapid response. The comparison between different characters of the diagnostic methods and the summary of the symptoms, incidence, and clinical strategies of complications given in this review are not only significant for the optimal use of diagnostic methods, but also beneficial for the prevention and management of complications.


Assuntos
Infecções por Coronavirus/diagnóstico , Pandemias , Pneumonia Viral/diagnóstico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Humanos , Incidência , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia
7.
Drug Des Devel Ther ; 14: 3625-3649, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982171

RESUMO

PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.

8.
Front Pharmacol ; 11: 891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32595510

RESUMO

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.

9.
Expert Opin Drug Metab Toxicol ; 16(9): 823-835, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32597258

RESUMO

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity. AREAS COVERED: Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery. EXPERT OPINION: Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.

10.
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.

11.
Eur J Pharmacol ; 874: 173022, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084420

RESUMO

Glioma is a kind of lethal malignant tumor, and lacks efficient therapies. Combination therapy has been claimed to be a promising approach to combat cancer, due to its increased anti-cancer effects and reduced side effects. This study aimed to investigate the anti-cancer effect and mechanism of combining imatinib with irinotecan or its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). First, we found that this drug combination exerted synergistic antitumor effects against glioma in vitro and in vivo. In addition, flow cytometry results proved that the SN-38-induced apoptosis was further enhanced by imatinib, and similar results were observed by determining the protein expression levels of apoptosis biomarkers. Interestingly, p53 expression was elevated by the SN-38 mono-treatment, and was not further increased after the co-treatment; besides, knockdown of p53 could only reduce the expression of cleaved-PARP partially, and weaken the enhanced proliferation inhibition induced by SN-38 plus imatinib, indicating that there might be other factors involved in the synergistic effects besides p53. Meanwhile, the markedly elevated p21 expression was observed only in the combination group, instead of the mono-treated groups. According to the results of p21 knockdown, we found that p21 was also required for the synergistic inhibitory effects. Moreover, we explored and ruled out the possibility of imatinib enhancing the sensitivity of irinotecan by inhibiting drug efflux pumps. Thus, our findings collectively suggest that combining irinotecan with imatinib could be a promising new strategy to fight against glioma.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioma/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Irinotecano/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Glioma/patologia , Humanos , Mesilato de Imatinib/farmacologia , Irinotecano/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Ratos , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
12.
Eur J Pharmacol ; 874: 173026, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088177

RESUMO

Cisplatin is a widely used chemotherapy drug that is first-line therapy for a variety of tumors. Unfortunately, its adverse effects on various normal tissues and organs, especially nephrotoxicity, threaten the life of patients. Although the mechanism of cisplatin nephrotoxicity has been confirmed to be related to oxidative stress, apoptosis of renal tubular epithelial cells and inflammatory response, there is no effective prevention strategy in the clinic. Here, we found that bisdemethoxycurcumin (BDMC), a natural compound, can significantly attenuates cisplatin-induced apoptosis of renal tubular epithelial cells in vitro at the concentration of 5-20 µM and has a significant protective effect on cisplatin-induced kidney injury in mice at the dose of 50 mg/kg. Mechanistically, BDMC attenuates cisplatin-induced apoptosis of renal tubular epithelial cells by inhibiting cisplatin-induced up-regulation of p53. Meanwhile, BDMC counteracts oxidative stress by inhibiting cisplatin-induced down-regulation of nuclear factor erythroid-2-related factor 2 (Nrf2). BDMC also significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) proteins, as well as the expression and translocation of the p65 subunit of nuclear factor-κB (NF-κB p65) into the nucleus, all of which were increased in the kidney by cisplatin treatment. Collectively, BDMC might be an effective prevention strategy which could against cisplatin-induced nephrotoxicity, and our research may shed a new light on treatment of drug toxicity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos , Antioxidantes/uso terapêutico , Cisplatino , Diarileptanoides/uso terapêutico , Nefropatias/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Quimiocina CCL2/metabolismo , Diarileptanoides/farmacologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Proteína Supressora de Tumor p53/metabolismo
13.
Toxicol Lett ; 319: 102-110, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706006

RESUMO

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased cleaved-caspase-8, a signaling protein of extrinsic apoptosis pathway, in a concentration and time-dependent manner. Moreover, we found the targets of crizotinib were not involved in HaCaT cells apoptosis. Collectively, our findings first report keratinocytes apoptosis is the key cause of crizotinib-induced cutaneous toxicity. We also reveal crizotinib induce apoptosis through the extrinsic apoptosis pathway due to detected up-regulated cleaved-caspase-8. Meanwhile, the apoptosis is independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Crizotinibe/toxicidade , Dermatite Esfoliativa/induzido quimicamente , Queratinócitos/efeitos dos fármacos , Clorometilcetonas de Aminoácidos/farmacologia , Caspase 8/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular , Dano ao DNA , Dermatite Esfoliativa/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Expert Rev Clin Pharmacol ; 12(12): 1121-1127, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31679411

RESUMO

Introduction: Sorafenib is a multitargeted tyrosine kinase inhibitor, which has been mainly used in the treatment of advanced hepatocellular carcinoma and renal cancer. However, hand-foot skin reaction (HFSR), as one of the most common adverse reactions, have hindered its long-term clinical application. At present, the mechanism of its occurrence has not been clearly studied and it leads to the lack of effective means of intervention. This article reviews known mechanism and management methods of HFSR caused by sorafenib.Areas covered: The author reviews HFSR caused by the treatment of sorafenib including the mechanism and management. English language reports located through PubMed are reviewed.Expert opinion: There are some conjectures about the mechanism of HFSR. However, the mechanism of HFSR induced by sorafenib is still unclear at present. In the absence of understanding the mechanism of HFSR, the most common method for clinical treatment of sorafenib-induced HFSR is dose down-regulation or discontinuation of treatment, which affects efficacy and even survival. Future research should focus on the mechanism of HFSR to find out new ways for prevention. Precautionary measures before the occurrence of HFSR can also be studied in the future.


Assuntos
Síndrome Mão-Pé/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Síndrome Mão-Pé/diagnóstico , Síndrome Mão-Pé/terapia , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe/administração & dosagem
16.
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
17.
Expert Opin Drug Metab Toxicol ; 15(9): 767-774, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478386

RESUMO

Introduction: The phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway has emerged as an important target in cancer therapy. Numerous PI3K/AKT/mTOR pathway inhibitors are extensively studied; some are used clinically, but most of these drugs are undergoing clinical trials. Potential adverse effects, such as severe hepatotoxicity and pneumonitis, have largely restricted the application and clinical significance of these inhibitors. A summary of mechanisms underlying the adverse effects is not only significant for the development of novel PI3K/AKT/mTOR inhibitors but also beneficial for the optimal use of existing drugs. Areas covered: We report a profile of the adverse effects, which we consider the class effects of PI3K/AKT/mTOR inhibitors. This review also discusses potential molecular toxicological mechanisms of these agents, which might drive future drug discovery. Expert opinion: Severe toxicities associated with PI3K/AKT/mTOR inhibitors hinder their approval and limit long-term clinical application of these drugs. A better understanding regarding PI3K/AKT/mTOR inhibitor-induced toxicities is needed. However, the mechanisms underlying these toxicities remain unclear. Future research should focus on developing strategies to reduce toxicities of approved inhibitors as well as accelerating new drug development. This review will be useful to clinical, pharmaceutical, and toxicological researchers.


Assuntos
Antineoplásicos/efeitos adversos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Humanos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
18.
J Vis Exp ; (149)2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31403631

RESUMO

In plant mitochondria, some steady-state transcripts have 5' triphosphate derived from transcription initiation (primary transcripts), while the others contain 5' monophosphate generated post-transcriptionally (processed transcripts). To discriminate between the two types of transcripts, several strategies have been developed, and most of them depend on presence/absence of 5' triphosphate. However, the triphosphate at primary 5' termini is unstable, and it hinders a clear discrimination of the two types of transcripts. To systematically differentiate and map the primary and processed transcripts stably accumulated in maize mitochondrion, we have developed a circular RT-PCR (cRT-PCR)-based strategy by combining cRT-PCR, RNA 5' polyphoshpatase treatment, quantitative RT-PCR (RT-qPCR), and Northern blot. As an improvement, this strategy includes an RNA normalization step to minimize the influence of unstable 5' triphosphate. In this protocol, the enriched mitochondrial RNA is pre-treated by RNA 5' polyphosphatase, which converts 5' triphsophate to monophosphate. After circularization and reverse transcription, the two cDNAs derived from 5' polyphosphatase-treated and non-treated RNAs are normalized by maize 26S mature rRNA, which has a processed 5' end and is insensitive to 5' polyphosphatase. After normalization, the primary and processed transcripts are discriminated by comparing cRT-PCR and RT-qPCR products obtained from the treated and non-treated RNAs. The transcript termini are determined by cloning and sequencing of the cRT-PCR products, and then verified by Northern blot. By using this strategy, most steady-state transcripts in maize mitochondrion have been determined. Due to the complicated transcript pattern of some mitochondrial genes, a few steady-state transcripts were not differentiated and/or mapped, though they were detected in a Northern blot. We are not sure whether this strategy is suitable to discriminate and map the steady-state transcripts in other plant mitochondria or in plastids.


Assuntos
Regulação da Expressão Gênica de Plantas/fisiologia , Mitocôndrias/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Zea mays/metabolismo , Northern Blotting , Proteínas de Plantas , RNA/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mitocondrial , RNA Ribossômico , Transcrição Genética
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...