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1.
Pharmacol Res ; 179: 106198, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35367343

RESUMO

Despite recent advances in diagnosis and therapeutic strategies, treatment of non-small-cell lung cancer (NSCLC) remains unsatisfactory in terms of prognosis. Andrographolide (AD), a principal active component of Andrographis paniculata (Burm.f.) Nees, exerts anti-cancer therapeutic properties. AD has been used for centuries in China for clinical treatment of viral infections. However, the pharmacological biology of AD in NSCLC remains unknown. In this study, AD regulated autophagy and PD-L1 expression in NSCLC. Molecular dynamics simulations indicated that AD bound directly to signal transducer and activator of transcription-3 (STAT3) with high affinity. Proteomics analysis indicated that AD reduced the expression of tumour PD-L1 in NSCLC by suppressing JAK2/STAT3 signalling. AD modulated the P62-dependent selective autophagic degradation of PD-L1 by inhibiting STAT3 phosphorylation. In vivo study revealed that AD suppressed tumour growth in H1975 xenograft mice and Lewis lung carcinoma cell models, and better efficacy was obtained at higher concentrations. AD prolonged the survival time of the mice and enhanced the treatment efficacy of anti-PD-1 mAb immunotherapy by stimulating CD8+ T cell infiltration and function. This work elucidated the specific mechanism by which AD inhibited NSCLC. Treatment with the combination of AD and anti-PD-1 mAb immunotherapy could be a potential strategy for patients with NSCLC.

2.
Chem Biol Drug Des ; 99(1): 83-91, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288496

RESUMO

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non-small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL)-mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c-Jun N-terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL-mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Naftiridinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Naftiridinas/química , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Cancer Lett ; 515: 36-48, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052328

RESUMO

Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.


Assuntos
Apigenina/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Luteolina/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interferon gama/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus
4.
Pharmacol Res ; 169: 105656, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964470

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. Therefore, new therapeutic agents are urgently needed to improve patient outcomes. Plumbagin (PLB), a natural sesquiterpene present in many Chinese herbal medicines, has been reported for its anti-cancer activity in various cancer cells. In this study, the effects and underlying mechanisms of PLB on the tumorigenesis of NSCLC were investigated. PLB dose-dependently inhibited the growth of NSCLC cell lines. PLB promoted ROS production, activated the endoplasmic reticulum (ER) stress pathway, and induced cell apoptosis, accompanied by the decreased expression level of ADP-ribosylation factor 1 (ARF1) in NSCLC cancer cells, and those effects of PLB could be reversed by the pretreatment with N-acetyl-L-cysteine (NAC). More importantly, the calcium chelator (BM) significantly reversed PLB-induced cell apoptosis. Furthermore, PLB significantly inhibited the growth of both H1975 xenograft and LLC1 tumors and exhibited antitumor activity by enhancing the number and the effector function of CD8+ T cells in KRASLA2 mice model and the LLC1 xenograft. Our findings suggest that PLB exerts potent antitumor activity against NSCLC in vitro and in vivo through ARF1 downregulation and induction of antitumor immune response, indicating that PLB is a new novel therapeutic candidate for the treatment of patients with NSCLC.


Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos Nus , Naftoquinonas/farmacologia , Transplante de Neoplasias
5.
J Exp Clin Cancer Res ; 39(1): 249, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33208183

RESUMO

BACKGROUND: Accumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC). METHODS: Cell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment. RESULTS: We showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8+ T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft, which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8+ T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice. CONCLUSIONS: Evodiamine can suppress NSCLC by elevating of CD8+ T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.


Assuntos
Mucina-1/metabolismo , Extratos Vegetais/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Quinazolinas/uso terapêutico , Animais , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação para Baixo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Extratos Vegetais/farmacologia , Quinazolinas/farmacologia , Transfecção
6.
Pharmacol Res ; 161: 105129, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32783976

RESUMO

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. However, there has been little improvement in its cure rate in the last 30 years, due to its intricate heterogeneity and drug resistance. Accumulating evidences have demonstrated that dysregulation of calcium (Ca2+) homeostasis contributes to oncogenesis and promotes tumor development. Inhibitors of Ca2+ channels/transporters to restore intracellular Ca2+ level were found to arrest tumor cell division, induce apoptosis, and suppress tumor growth both in vitro and in vivo. Dolutegravir (DTG), which is a first-line drug for Acquired Immune Deficiency Syndrome (AIDs) treatment, has been shown to increase intracellular Ca2+ levels and Reactive oxygen species (ROS) levels in human erythrocytes, leading to suicidal erythrocyte death or eryptosis. To explore the potential of DTG as an antitumor agent, we have designed and synthesized a panel of compounds based on the principle of biologically active substructure splicing of DTG. Our data demonstrated that 7-methoxy-4-methyl-6,8-dioxo-N-(3-(1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (DTHP), a novel derivative of DTG, strongly inhibited the colony-forming ability and proliferation of NSCLC cells, but displayed no cytotoxicity to normal lung cells. DTHP treatment also induced apoptosis and upregulate intracellular Ca2+ level in NSCLC cells significantly. Inhibiting Ca2+ signaling alleviated DTHP-induced apoptosis, suggesting the perturbation of intracellular Ca2+ is responsible for DTHP-induced apoptosis. We further discovered that DTHP activates AMPK signaling pathway through binding to SERCA, a Ca2+-ATPase. On the other hand, DTHP treatment promoted mitochondrial ROS production, causing mitochondrial dysfunction and cell death. Finally, DTHP effectively inhibited tumor growth in the mouse xenograft model of lung cancer with low toxicity to normal organs. Taken together, our work identified DTHP as a superior antitumor agent, which will provide a novel strategy for the treatment of NSCLC with potential clinical application.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Oxazinas/farmacologia , Piperazinas/farmacologia , Piridonas/farmacologia , Células A549 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Chin Med ; 15: 70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32665783

RESUMO

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently was declared a pandemic by world health organization (WHO) Due to sudden outbreaks, currently, no completely effective vaccine or drug is clinically approved. Several therapeutic strategies can be envisaged to prevent further mortality and morbidity. Based on the past contribution of traditional Chinese medicines (TCM) and immune-based therapies as a treatment option in crucial pathogen outbreaks, we aimed to summarize potential therapeutic strategies that could be helpful to stop further spread of SARS-CoV-2 by effecting its structural components or modulation of immune responses. Several TCM with or without modification could be effective against the structural protein, enzymes, and nucleic acid should be tested from available libraries or to identify their immune-stimulatory activities to enhance several antiviral biological agents for effective elimination of SARS-CoV-2 from the host. TCM is not only effective in the direct inhibition of virus attachment and internalization in a cell but can also prevent their replication and can also help to boost up host immune response. Immune-modulatory effects of TCMs may lead to new medications and can guide us for the scientific validity of drug development. Besides, we also summarized the effective therapies in clinical for controlling inflammation. This review will be not only helpful for the current situation of COVID-19, but can also play a major role in such epidemics in the future.

8.
Pharmacol Res ; 159: 104934, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32464330

RESUMO

Tyrosine kinase inhibitors (TKIs) have been widely used for the clinical treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. Unfortunately, due to the secondary mutation in EGFR, eventual drug-resistance is inevitable. Therefore, to overcome the resistance, new agent is urgently required. Chelidonine, extracted from the roots of Chelidonium majus, was proved to effectively suppress the growth of NSCLC cells with EGFR double mutation. Proteomics analysis indicated that mitochondrial respiratory chain was significantly inhibited by chelidonine, and inhibitor of AMPK effectively blocked the apoptosis induced by chelidonine. Molecular dynamics simulations indicated that chelidonine could directly bind to EGFR and showed a much higher binding affinity to EGFRL858R/T790M than EGFRWT, which demonstrated that chelidonine could selectively inhibit the phosphorylation of EGFR in cells with EGFR double-mutation. In vivo study revealed that chelidonine has a similar inhibitory effect like second generation TKI Afatinib. In conclusion, targeting EGFR and inhibition of mitochondrial function is a promising anti-cancer therapeutic strategy for inhibiting NSCLC with EGFR mutation and TKI resistance.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Mutação , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Shanghai Kou Qiang Yi Xue ; 18(6): 599-603, 2009 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-20143021

RESUMO

PURPOSE: To investigate the effect of mechanical strain on cell morphology, viability and proliferation of human dental pulp cells in vitro. METHODS: Human dental pulp cells were cultured and subjected to 2% or 8% strain with Flexcell Tension Plus System for 0.5 hour, 12 hours and 24 hours, respectively, and then the cell morphology, viability and proliferation were examined by phase contrast microscope, trypan-blue staining and MTT method. The results were analyzed by one-way ANOVA with SPSS16.0 software package. RESULTS: Cells were stretched and aligned perpendicular to the direction of the force applied with obvious pole formation under the tested condition. The viability and proliferation of the cells subjected 2% or 8% strain were significantly higher than that of untreated cells, which reached the peak at 12 hours. The proliferation of the cells increased after loading strain which was significantly higher than that in the control by 2% stain subjected for 24 hours (P<0.01). CONCLUSIONS: Cyclic strain could affect morphology, viability and proliferation of in vitro cultured human dental pulp cells in a magnitude/time dependent manner.


Assuntos
Proliferação de Células , Células Cultivadas , Polpa Dentária , Humanos , Técnicas In Vitro
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