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1.
Phytomedicine ; : 153831, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34794861

RESUMO

BACKGROUND: Currently, the identification of accurate biomarkers for the diagnosis of patients with early-stage lung cancer remains difficult. Fortunately, metabolomics technology can be used to improve the detection of plasma metabolic biomarkers for lung cancer. In a previous study, we successfully utilised machine learning methods to identify significant metabolic markers for early-stage lung cancer diagnosis. However, a related research platform for the investigation of tumour metabolism and drug efficacy is still lacking. HYPOTHESIS/PURPOSE: A novel methodology for the comprehensive evaluation of the internal tumour-metabolic profile and drug evaluation needs to be established. METHODS: The optimal location for tumour cell inoculation was identified in mouse chest for the non-traumatic orthotopic lung cancer mouse model. Microcomputed tomography (micro-CT) was applied to monitor lung tumour growth. Proscillaridin A (P.A) and cisplatin (CDDP) were utilised to verify the anti-lung cancer efficacy of the platform. The top five clinically valid biomarkers, including proline, L-kynurenine, spermidine, taurine and palmitoyl-L-carnitine, were selected as the evaluation indices to obtain a suitable lung cancer mouse model for clinical metabolomics research by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The platform was successfully established, achieving 100% tumour development rate and 0% surgery mortality. P.A and CDDP had significant anti-lung cancer efficacy in the platform. Compared with the control group, four biomarkers in the orthotopic model and two biomarkers in the metastatic model had significantly higher abundance. Principal component analysis (PCA) showed a significant separation between the orthotopic/metastatic model and the control/subcutaneous/KRAS transgenic model. The platform was mainly involved in arginine and proline metabolism, tryptophan metabolism, and taurine and hypotaurine metabolism. CONCLUSION: This study is the first to simulate clinical metabolomics by comparing the metabolic phenotype of plasma in different lung cancer mouse models. We found that the orthotopic model was the most suitable for tumour metabolism. Furthermore, the anti-tumour drug efficacy was verified in the platform. The platform can very well match the clinical reality, providing better lung cancer diagnosis and securing more precise evidence for drug evaluation in the future.

2.
Phytomedicine ; : 153786, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34785104

RESUMO

BACKGROUND: Lung cancer has become the principal cause of cancer-related deaths. Emodin is a Chinese herb-derived compound extracted from the roots of Rheum officinale that exhibits numerous pharmacological characteristics. Secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in cancers and plays an important role in cancer development. PURPOSE: This study aims to investigate the anti-tumor mechanism of emodin in non-small-cell lung cancer (NSCLC). METHODS: MTT assay was applied to detect the sensitivity of emodin to NSCLC cell line. Flow cytometry was used to examine the effect of emodin on cell cycle distribution and evaluate ROS level and apoptosis. Western blot analysis was utilised to examine the expression levels of sPLA2-IIa, PKM2, and AMPK and its downstream pathways induced by emodin. Enzyme inhibition assay was applied to investigate the inhibitory effect of emodin on sPLA2-IIa. The anticancer effect of emodin was also detected using an in vivo model. RESULTS: Emodin significantly inhibited NSCLC proliferation in vivo and in vitro and was relatively less cytotoxic to normal lung cell lines. Most importantly, emodin inhibited the proliferation of KRAS mutant cell lines by decreasing the expression of sPLA2-IIa and NF-κB pathways. Emodin also inhibited mTOR and AKT and activated the AMPK pathway. Furthermore, emodin induced apoptosis, increased the reactive oxygen species (ROS) level, and arrested the cell cycle. CONCLUSION: Emodin exhibited a novel anti-tumor mechanism of inhibiting the proliferation of KRAS mutant cell lines by decreasing the expression levels of sPLA2-IIa and NF-κB pathways. Hence, emodin can potentially serve as a therapeutic target in NSCLC.

3.
Oncol Lett ; 22(5): 787, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34594428

RESUMO

Lung cancer is the most common type of cancer with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of lung cancer cases. In the past two decades, immunotherapy has become a more promising treatment method than traditional treatments (surgery, radiotherapy and chemotherapy). Immunotherapy has been shown to improve the survival rate of patients and to have a superior effect when controlling lung cancer than traditional therapy. However, only a small number of patients can benefit from immunotherapy, and not all patients who qualify experience long-term benefits. In the clinic, the objective response rate of programmed cell death protein 1 treatment without the prior screening of patients is only 15-20%. Immunotherapy is associated with both opportunities and challenges for patients with NSCLC. The current challenges of immunotherapy include the lack of accurate biomarkers, inevitable resistance and insufficient understanding of immune checkpoints. In previous years, several methods for overcoming the challenges posed by immunotherapy have been proposed, but combination therapy is the most suitable choice. A large number of studies have shown that the combination of drugs can significantly improve their efficacy, compared with monotherapy, and that some therapeutic combinations have been approved by the Food and Drug Administration for the treatment of NSCLC. Traditional Chinese medicine (TCM) is a traditional medical practice in China that can play an important role in immunotherapy. Most agents used in TCM originate from plants, and have the advantages of low toxicity and multiple targets. In addition, TCM includes a unique class of drugs that can improve autoimmunity. Therefore, TCM may be a promising treatment method for all types of cancer.

4.
Pharmacol Res ; 171: 105574, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34419228

RESUMO

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients.

5.
BMC Cancer ; 21(1): 531, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971846

RESUMO

BACKGROUND: Cervical cancer continues to be one of the leading causes of cancer deaths among females in low and middle-income countries. In this study, we aimed to assess the independent prognostic value of clinical and potential prognostic factors in progression-free survival (PFS) in cervical cancer. METHODS: We conducted a retrospective study on 92 cervical cancer patients treated from 2017 to 2019 at the Zhuhai Hospital of Traditional Chinese and Western Medicine. Tumor characteristics, treatment options, progression-free survival and follow-up information were collected. Kaplan-Meier method was used to assess the PFS. RESULTS: Results showed that the number of retrieved lymph nodes had a statistically significant effect on PFS of cervical cancer patients (P = 0.002). Kaplan-Meier survival curve analysis showed that cervical cancer patients with initial symptoms age 25-39 had worse survival prognoses (P = 0.020). And the using of uterine manipulator in laparoscopic treatment showed a better prognosis (P < 0.001). A novel discovery of our study was to verify the prognostic values of retrieved lymph nodes count combining with FIGO staging system, which had never been investigated in cervical cancer before. According to the Kaplan-Meier survival curve analysis and receiver operating characteristic (ROC) curve analysis, significant improvements were found after the combination of retrieved lymph nodes count and FIGO stage in predicting PFS for cervical cancer patients (P < 0.001, AUC = 0.826, 95% CI: 0.689-0.962). CONCLUSION: Number of retrieved lymph nodes, initial symptoms age, uterine manipulator, and retrieved lymph nodes count combining with FIGO staging system could be potential prognostic factors for cervical cancer patients.


Assuntos
Neoplasias do Colo do Útero/mortalidade , Adulto , Idoso , Feminino , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia
6.
Antioxid Redox Signal ; 34(14): 1108-1127, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33115253

RESUMO

Recent Advances: The 2019 Nobel Prize awarded to the mechanisms for oxygen sensing and adaptation according to oxygen availability, highlighting the fundamental importance of gaseous molecules. Gaseous molecules, including reactive oxygen species (ROS), can interact with different cations generated during metabolic and redox dysregulation in cancer cells. Cross talk between calcium signaling and metabolic/redox pathways leads to network-based dyregulation in cancer. Significance: Recent discovery on using small molecules targeting the ion channels, redox signaling, and protein modification on metabolic enzymes can effectively inhibit cancer growth. Several FDA-approved drugs and clinical trials are ongoing to target the calcium channels, such as TRPV6 and TRPM8. Multiple small molecules from natural products target metablic and redox enzymes to exert an anticancer effect. Critical Issues: Small molecules targeting key ion channels, metabolic enzymes that control key aspects of metabolism, and redox proteins are promising, but their action mechanisms of the target are needed to be elucidated with advanced-omic technologies, which can give network-based and highly dimensioal data. In addition, small molecules that can directly modify the protein residues have emerged as a novel anticancer strategy. Future Directions: Advanced technology accelerates the detection of ions and metabolic and redox changes in clinical samples for diagnosis and informs the decision of cancer treatment. The improvement of ROS detection, ROS target identification, and computational-aid drug discovery also improves clincal outcome.Overall, network-based or holistic regulations of cancer via ion therapy and metabolic and redox intervention are promising as new anticancer strategies. Antioxid. Redox Signal. 34, 1108-1127.

7.
Transl Oncol ; 14(1): 100907, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33217646

RESUMO

Early diagnosis has been proved to improve survival rate of lung cancer patients. The availability of blood-based screening could increase early lung cancer patient uptake. Our present study attempted to discover Chinese patients' plasma metabolites as diagnostic biomarkers for lung cancer. In this work, we use a pioneering interdisciplinary mechanism, which is firstly applied to lung cancer, to detect early lung cancer diagnostic biomarkers by combining metabolomics and machine learning methods. We collected total 110 lung cancer patients and 43 healthy individuals in our study. Levels of 61 plasma metabolites were from targeted metabolomic study using LC-MS/MS. A specific combination of six metabolic biomarkers note-worthily enabling the discrimination between stage I lung cancer patients and healthy individuals (AUC = 0.989, Sensitivity = 98.1%, Specificity = 100.0%). And the top 5 relative importance metabolic biomarkers developed by FCBF algorithm also could be potential screening biomarkers for early detection of lung cancer. Naïve Bayes is recommended as an exploitable tool for early lung tumor prediction. This research will provide strong support for the feasibility of blood-based screening, and bring a more accurate, quick and integrated application tool for early lung cancer diagnostic. The proposed interdisciplinary method could be adapted to other cancer beyond lung cancer.

8.
J Cancer Res Clin Oncol ; 146(6): 1441-1450, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248302

RESUMO

INTRODUCTION: Poliovirus receptor (PVR) is a tumor promoter and a regulatory checkpoint that enhances immunosuppression. We investigated PVR expression by applying immunohistochemistry (IHC) staining. A positive association existed between PVR expression and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expression in patients with surgically resected non-small-cell lung cancer (NSCLC). PVR expression is a prognosis predictor of lung adenocarcinoma. PURPOSE: To investigate the prognostic significance of PVR expression and CTLA4 expression for surgically resected NSCLC. PATIENTS AND METHODS: The medical records of 108 Chinese patients with primary NSCLC who underwent surgery were retrospectively reviewed. The expression of PVR and CTLA4 were measured through IHC. Clinical characteristics, the association between PVR and CTLA4, and the prognostic significance of PVR were analyzed. RESULTS: A significant positive association was observed between PVR and CTLA4 expression in NSCLC (P = 0.016). PVR had a high positive rate among females, nonsmokers, and patients with adenocarcinoma and advanced lung cancer. The overall survival (OS) of patients with negative PVR expression was significantly longer than that of patients with positive PVR expression (P = 0.049), especially among females (P = 0.03) and nonsmokers (P = 0.025). Multivariate analysis results showed that advanced tumor stage and PVR expression were independent prognosis predictors of poor OS. CONCLUSION: PVR can potentially serve as a prognostic predictor and biomarker for NSCLC and cancer anti-CTLA4 immunotherapy response.


Assuntos
Antígeno CTLA-4/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores Virais/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
9.
Int J Oncol ; 56(2): 470-479, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894264

RESUMO

microRNAs (miRNAs or miRs) are endogenous noncoding single­stranded RNA molecules that can regulate gene expression by targeting the 3'­untranslated region and play an important role in many biological and pathological processes, such as inflammation and cancer. In this study, we found that miR­20b was significantly increased in human non­small cell lung cancer (NSCLC) cell lines and patient tissues, suggesting that it may possess a carcinogenic role in lung cancer. This miRNA promoted the proliferation, migration and invasion of NSCLC cells by targeting and downregulating the expression of adenomatous polyposis coli (APC), which is a negative regulator of the canonical Wnt signaling pathway. Wnt signaling activation may increase transcription of miR­20b. Therefore, miR­20b and canonical Wnt signaling were coupled through a feed­forward positive feedback loop, forming a biological regulatory circuit. Finally, an in vivo investigation further demonstrated that an increase in miR­20b promoted the growth of cancer cells. Overall, our findings offer evidence that miR­20b may contribute to the development of NSCLC by inhibiting APC via the canonical Wnt signaling pathway.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt/genética , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica , Voluntários Saudáveis , Humanos , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Pneumonectomia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
BMC Genomics ; 21(1): 22, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910818

RESUMO

BACKGROUND: Early sex differentiation genes of zebrafish remain an unsolved mystery due to the difficulty to distinguish the sex of juvenile zebrafish. However, aromatase inhibitors (AIs) could direct juvenile zebrafish sex differentiation to male and even induce ovary-to-testis reversal in adult zebrafish. RESULTS: In order to determine the transcriptomic changes of sex differentiation in juvenile zebrafish and early sex-reversal in adult zebrafish, we sequenced the transcriptomes of juvenile and adult zebrafish treated with AI exemestane (EM) for 32 days, when juvenile zebrafish sex differentiation finished. EM treatment in females up-regulated the expression of genes involved in estrogen metabolic process, female gamete generation and oogenesis, including gsdf, macf1a and paqr5a, while down-regulated the expression of vitellogenin (vtg) genes, including vtg6, vtg2, vtg4, and vtg7 due to the lower level of Estradiol (E2). Furthermore, EM-juveniles showed up-regulation in genes related to cell death and apoptosis, such as bcl2l16 and anax1c, while the control-juveniles exhibited up-regulation of genes involved in positive regulation of reproductive process and oocyte differentiation such as zar1 and zpcx. Moreover, EM-females showed higher enrichment than control females in genes involved in VEGF signaling pathway, glycosaminoglycan degradation, hedgehog signaling pathway, GnRH signaling pathway and steroid hormone biosynthesis. CONCLUSIONS: Our study shows anti-masculinization in EM-treated adult females but not in EM-treated juveniles. This may be responsible for the lower sex plasticity in adults than juveniles.


Assuntos
Inibidores da Aromatase/farmacologia , Diferenciação Sexual/genética , Vitelogênese/genética , Vitelogeninas/genética , Peixe-Zebra/genética , Androstadienos/farmacologia , Animais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Hedgehog/genética , Masculino , Reprodução/genética , Diferenciação Sexual/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vitelogênese/efeitos dos fármacos
11.
Chin J Dent Res ; 23(4): 297-307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33491362

RESUMO

Ideally, orthognathic surgery is indicated to treat skeletal Class III malocclusion with severe open bite in adults. In this borderline case, however, camouflage treatment without any skeletal anchorage was chosen. This report describes the orthodontic treatment of a 23-year-old man who presented with multiple orthodontic problems including severe open bite of the anterior and posterior teeth up to the first molars, bilateral posterior crossbite, bilateral Class III molar relationship, severe crowding, increased vertical dimension, and dental and facial midline deviation. The treatment included the extraction of four wisdom teeth, uprighting and distalisation of the mandibular arch with molar intrusion using curved NiTi wires with intermaxillary elastics. After 36 months of treatment, satisfactory improvements in the vertical overlap, horizontal overlap and sagittal malocclusion were achieved. The design of the mechanical system used in this case confirmed stable results at the 4-year follow-up.


Assuntos
Má Oclusão , Mordida Aberta , Procedimentos de Ancoragem Ortodôntica , Adulto , Cefalometria , Seguimentos , Humanos , Masculino , Mandíbula , Mordida Aberta/terapia , Técnicas de Movimentação Dentária , Adulto Jovem
12.
Integr Cancer Ther ; 18: 1534735419890020, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31838881

RESUMO

Conventional methods in treating non-small cell lung cancer contain surgery, chemotherapy, radiotherapy, and targeted therapy, which have various defects. Recently, with the deeper research on tumor immunity, immunotherapy has made the breakthrough in the treatment of cancers. Especially developments of programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the therapy into a new stage. This review mainly focuses on introducing existing monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1 expression, tumor mutation burden, and microsatellite instability. By understanding the resistance mechanism of anti-PD-1/L1 blockade, research is further improving the survival benefit and expanding the benefit population. So, PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies clinically. Discussion and comparison of their effectiveness and safety are also comprehensively reviewed. Meanwhile, we explore the potential, the impact, and mechanisms of combining traditional Chinese medicine with immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/metabolismo , Humanos , Imunoterapia/métodos , Medicina Tradicional Chinesa/métodos
13.
Cell Death Dis ; 10(11): 821, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659154

RESUMO

MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated protein 1(KEAP1) expression by targeting its 3'-untranslated region (3'UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, ß-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting ß-catenin reduced miR-421 levels in A549 cells. In addition, ß-catenin upregulation enhanced miR-421 expression, indicating that ß-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , MicroRNAs/genética , Paclitaxel/administração & dosagem , Regiões 3' não Traduzidas/genética , Células A549 , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Xenoenxertos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos
14.
Cell Death Dis ; 9(6): 696, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899551

RESUMO

Non-small-cell lung cancer (NSCLC) is the predominant histological type of lung cancer and is characterized by the highest mortality and incidence rates among these types of malignancies. Cardiac glycosides, a class of natural products, have been identified as a potential type of chemotherapeutic agent. This study aims to investigate the anti-cancer effects and the mechanisms of action of Proscillaridin A (P.A) in NSCLC cells. In vitro sodium-potassium pump (Na+/K+ ATPase) enzyme assays indicated that P.A is a direct Na+/K+ ATPase inhibitor. P.A showed potent cytotoxic effects in NSCLC cells at nanomolar levels. Treatment mechanism studies indicated that P.A elevated Ca2+ levels, activated the AMPK pathway and downregulated phosphorylation of ACC and mTOR. Subsequently, P.A increased death receptor 4 (DR4) expression and downregulated NF-κB. Interestingly, P.A selectively suppressed EGFR activation in EGFR mutant cells but not in EGFR wild-type cells. In vivo, P.A significantly suppressed tumor growth in nude mice compared to vehicle-treated mice. Compared with the Afatinib treatment group, P.A displayed less pharmaceutical toxicity, as the body weight of mice treated with P.A did not decrease as much as those treated with Afatinib. Consistent changes in protein levels were obtained from western blotting analysis of tumors and cell lines. Immunohistochemistry analysis of the tumors from P.A-treated mice showed a significant suppression of EGFR phosphorylation (Tyr 1173) and reduction of the cell proliferation marker Ki-67. Taken together, our results suggest that P.A is a promising anti-cancer therapeutic candidate for NSCLC.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proscilaridina/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima/efeitos dos fármacos , Acetil-CoA Carboxilase/metabolismo , Adenilato Quinase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Pulmonares/metabolismo , Modelos Biológicos , Mutação/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Proscilaridina/química , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Chem Biol Drug Des ; 92(5): 1851-1858, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29931766

RESUMO

Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore, we aimed to identify new compounds that might act as pyruvate kinase M2 isoform (PKM2) activators and to investigate their anti-cancer efficacy in non-small-cell lung cancer (NSCLC) cells. The molecular docking method was applied to screen PKM2 activators from our virtual natural products library. Then, compounds with promising docking scores were examined for cytotoxic effects in a panel of NSCLC cells using the MTT assay. Functional effects and therapeutic mechanisms were investigated by in vitro enzyme assays, western blotting (WB), and flow cytometry. Molecular docking showed that 0089-0022 acts as a potential PKM2 activator by binding to the kinase pocket. An in vitro enzyme activity assay showed that 0089-0022 is a direct PKM2 activator and that it effectively induces apoptosis in A549 and H1975 cells through inhibition of AKT phosphorylation. Our results suggest that 0089-0022 activates PKM2 and thus is a promising anti-cancer therapeutic candidate in NSCLC.


Assuntos
Antineoplásicos/química , Piruvato Quinase/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piruvato Quinase/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
16.
Front Pharmacol ; 9: 558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29892225

RESUMO

Honokiol is a natural compound with small molecular structure and extracted from bark of magnolia trees. The biological activities of honokiol include anti-oxidation, anti-inflammation as well as anti-tumor. However, their mechanism remains unknown. In this study, A549 cell line and EGFR-mutant cell line PC-9 with higher expression level of Lyn than A549 cells were used to assess the anti-tumor effects of honokiol. As shown in this study, honokiol is an effective drug on inhibiting proliferation and inducing apoptosis depended on Lyn and EGFR signal pathway regulated by Lyn, and its efficacy is stronger in PC-9 cells than A549 cells. In addition, this anti-tumor effect in PC-9 cells was weakened by Lyn-knockdown. Taken together, this study indicated the mechanism of honokiol on lung adenocarcinoma and provides a possibility of honokiol as an effective anti-tumor medicine.

17.
Front Pharmacol ; 8: 199, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28443025

RESUMO

Aberrant signaling transduction induced by mutant KRAS proteins occurs in 20∼30% of non-small cell lung cancer (NSCLC), however, a direct and effective pharmacological inhibitor targeting KRAS has not yet reached the clinic to date. Honokiol, a small molecular polyphenol natural biophenolic compound derived from the bark of magnolia trees, exerts anticancer activity, however, its mechanism remains unknown. In this study, we sought to investigate the in vitro effects of honokiol on NSCLC cell lines harboring KRAS mutations. Honokiol was shown to induce G1 arrest and apoptosis to inhibit the growth of KRAS mutant lung cancer cells, which was weakened by an autophagy inhibitor 3-methyladenine (3-MA), suggesting a pro-apoptotic role of honokiol-induced autophagy that was dependent on AMPK-mTOR signaling pathway. In addition, we also discovered that Sirt3 was significantly up-regulated in honokiol treated KRAS mutant lung cancer cells, leading to destabilization of its target gene Hif-1α, which indicated that the anticancer property of honokiol maybe regulated via a novel mechanism associated with the Sirt3/Hif-1α. Taken together, these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM).

18.
J Thorac Dis ; 8(8): 2203-11, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27621877

RESUMO

BACKGROUND: Pneumoconiosis is one of the most common occupational diseases, which shows the progressive and irreversible pathological changes. It ultimately can induce pulmonary failure and lead to death. To date, these patients have no curative treatment option under the current standard of care, so it is especially important to delay the onset of the disease and slow down its progression. Therefore, understanding of clinical features of pneumoconiosis is particularly critical for medical intervention. METHODS: We collected the clinical data from 118 pneumoconiosis cases of miners admitted in hospital and processed the statistics analysis by using the Chi-square test and the risk assessment. RESULTS: Compared to other types of miners, gold miners are liable to cause Broncho-pulmonary co-infection with Chi-square value 18.748 and the P value <0.001. However, unexpectedly, the smoking miners displayed a better Activities of Daily Living (ADLs) compared to non-smokers, which showed 19.318 of Chi-square score and less than 0.001 of P value. And this connection was associated with the dust exposure time (P<0.05), showing the increasing risk of non-smoking miners occurred as the increasing time exposed to dust. In addition, our analysis indicated that the probability of smoking miners suffered from Broncho-pulmonary co-infection was less than non-smoking miners with Chi-square value 8.044 and P<0.01, which was also associated with the dust exposure time tendentiously, though P>0.05. Moreover, smoking history exhibited a deteriorating effect to the overall survival (OS) with 9.546 of Chi-square value and P<0.05, in accordance with smoking reducing life time. Interestingly, pneumoconiosis drugs could extend the smokers' OS, but not non-smokers'. CONCLUSIONS: Our studies suggest that the history of smoking and exposure time of dust play important roles in the development of pneumoconiosis and smoking could be a factor that determines the treatment options depending on patients' smoking history.

19.
Oncotarget ; 7(26): 39970-39979, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-27223066

RESUMO

The discovery of Warburg effect opens a new era in anti-cancer therapy. Aerobic glycolysis is regarded as a hallmark of cancer cells and increasing literatures indicates that metabolic changes are critical for the maintenance and progression of cancer cells. Besides aerobic glycolysis, increased fatty acid synthesis is also required for the rapid growth of cancer cells, and is considered as one of the most typical metabolic symbols of cancer either. Thus, targeting fatty acid metabolism may provide a potential avenue for the diagnosis and therapeutic treatment of cancer. In this study, we have identified Sterol-CoA desaturase-1 (SCD1) which is the rate-limiting enzyme of unsaturated fatty acid synthesis, universally and highly expressed in lung adenocarcinoma and was required for the cell proliferation, migration and invasion. Both in vitro and in vivo studies demonstrated that high expression of SCD1 remarkably enhanced the ability of tumor formation and invasion, while knockdown of SCD1 significantly repressed tumorigenesis and induced cell apoptosis. Clinical association study suggested that high expression of SCD1 is more frequently observed in late stage patients and presents poor prognosis. Taken together, our results suggested that SCD1 is a potentially novel biomarker of lung adenocarcinoma, and targeting SCD1 may represent a new anti-cancer strategy.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica , Ácidos Graxos/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Prognóstico , Resultado do Tratamento
20.
Opt Express ; 17(19): 16379-84, 2009 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-19770851

RESUMO

K-shell x-ray at about 3 keV emitted from Ar clusters irradiated by 110 mJ 55 fs intense laser pulses is studied. The x-ray flux is optimized by moving the nozzle away from the focus of the laser pulse. The total flux of K-shell x-ray photons in 4pi reaches a maximum of 4.5x10(9) photons/shot with a conversion efficiency of 2.5x10(-5) when the nozzle displacement is 2 mm and a long plasma channel is observed by a probe beam.

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