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1.
Molecular mechanisms of natural compounds in cell death induction and sensitization to chemotherapeutic drugs in lung cancer.
Wattanathamsan, O, Hayakawa, Y, Pongrakhananon, V
Phytotherapy research : PTR. 2019;(10):2531-2547
Abstract
Cancer remains one of the leading causes of death worldwide, especially lung cancer. Chemotherapeutic drugs are commonly used for lung cancer treatment; nonetheless, undesirable side effects and drug resistance remain major challenges for therapeutic success. Therefore, harmless and effective treatments against lung cancer are urgently required. The use of natural phytochemical products, in single or combinatorial therapy, is an emerging strategy for prevention and cure of cancer because of the various remarkable anticancer properties of these compounds. Cell death, which primarily occurs via apoptosis and nonapoptotic mechanisms (necrosis, autophagy, and cellular senescence), is one of the antineoplastic effects of natural compounds. In this review, we highlight representative plant-derived compounds with cancer chemopreventive and sensitizing effects in combination with chemotherapeutic drugs with various cell death-inducing mechanisms. Relevant molecular mechanisms implicated in the pharmacological effects of these natural compounds are discussed. Overall, this review provides a reference and new perspective for application of phytochemical agents as potential anti-lung cancer drugs for further cancer drug research and development.
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2.
NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype.
Bocci, F, Tripathi, SC, Vilchez Mercedes, SA, George, JT, Casabar, JP, Wong, PK, Hanash, SM, Levine, H, Onuchic, JN, Jolly, MK
Integrative biology : quantitative biosciences from nano to macro. 2019;(6):251-263
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Abstract
The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the 'metastatic sweet spot'.
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Study of the metabolomic relationship between lung cancer and chronic obstructive pulmonary disease based on direct infusion mass spectrometry.
Callejón-Leblic, B, Pereira-Vega, A, Vázquez-Gandullo, E, Sánchez-Ramos, JL, Gómez-Ariza, JL, García-Barrera, T
Biochimie. 2019;:111-122
Abstract
The high prevalence of lung cancer (LC) has triggered the search of biomarkers for early diagnosis of this disease. For this purpose the study of metabolic changes related to the development of lung cancer could provide interesting information about its early diagnosis. In this sense, chronic obstructive pulmonary disease (COPD), a disease associated with tumor development, is a comorbidity that increases the risk of onset and progression of lung neoplasia and has also to be considered in the study of pathology related to lung cancer. This work develop a metabolomic approach based on direct infusion mass spectrometry using a hybrid triple quadrupole-time of flight mass spectrometer (DI-ESI-QqQ-TOF-MS) in order to identify altered metabolites from serum of LC and COPD patients and evaluate its relationship and implication in the progression of LC. This methodology has been applied to 30 serum samples from LC, 30 healthy patients used as controls (HC) and 30 serum samples from COPD to found altered metabolites from both LC and COPD diseases. In addition, some metabolic differences and similarities were found in Pulmonary Emphysema and Chronic Bronchitis patients. On the other hand, altered metabolites were studied in different stages of LC (II, III and IV) to evaluate the perturbation of them throughout the progression of disease. The sample treatment consisted of the extraction of polar and non-polar metabolites from serum that was later infused into the mass spectrometer using an electrospray ionization source in positive and negative mode. Partial least squares discriminant analysis (PLS-DA) allowed a classification between LC, HC and COPD groups in all acquisition modes. A total of 35 altered and common metabolites between LC and COPD, including amino acids, fatty acids, lysophospholipids, phospholipids and triacylglycerides were identified, being alanine, aspartate and glutamate metabolism the most altered. Finally, ROC curves were applied to the dataset and metabolites with AUC value higher than 0.70 were considered as relevant in the progression of LC.
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Energy spectrum computed tomography improves the differentiation between benign and malignant solitary pulmonary nodules.
Zhao, J, Chai, Y, Zhou, J, Zhang, Z, Wang, Z
Clinical and investigative medicine. Medecine clinique et experimentale. 2019;(3):E40-E46
Abstract
PURPOSE To evaluate the diagnostic efficiency of computed tomography (CT) values at the 40~140 keV monochromatic level for the differential diagnosis of solitary pulmonary nodules (SPNs). METHODS Energy spectrum CT data of 44 patients with SPNs were analyzed retrospectively; 24 patients with malignant SPNs served as the malignant group and 20 patients with benign SPNs served as the benign group. The basic material concentration and the enhancement degree differences in double-phase enhanced scans were compared between the two groups. The sensitivity and specificity were calculated to determine diagnosis, and were compared with the pathology results. RESULTS The CT values at the 40~90 keV monochromatic level and the iodine concentrations of malignant group were higher than those of benign group in the arterial phase (all P < 0.05). The enhancement degree of the malignant group was higher than that for the benign group in the arterial phase (36.36 ± 33.18 HU vs 16.93 ± 24.17 HU t = 2.243, P = 0.030); however, the enhancement degrees of the two groups were similar in the venous phase (21.99 ± 15.87 HU vs 17.62 ± 24.15 HU t = 0.694, P = 0.493). The area under the curve of the enhancement degree in the arterial phase was 0.792. CONCLUSIONS Monochromatic imaging and base material concentration of energy spectrum CT can help differentiate between benign and malignant SPNs.
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The Effects of Dietary Supplements on Asthma and Lung Cancer Risk in Smokers and Non-Smokers: A Review of the Literature.
Alsharairi, NA
Nutrients. 2019;(4)
Abstract
Smoking is one of the major global causes of death. Cigarette smoke and secondhand (passive) smoke have been causally related to asthma and lung cancer. Asthma is a potential risk factor for developing lung cancer in both smokers and non-smokers. Prospective studies and randomized control trials (RCTs) of dietary supplements and lung cancer risk in adult smokers and non-smokers have yielded inconsistent results. A few prospective studies have shown that long-term use of high doses of some supplements, such as retinol, β-carotene, B vitamins, and vitamin E, increase lung cancer risk in current and former smokers. Limited evidence from RCTs suggests that vitamin D supplementation is effective in improving lung function and reducing asthma risk in current/former smokers. The relationship between dietary supplements and lung cancer risk has never before been examined in asthmatic smokers and non-smokers. This short review aims to examine the evidence from existing studies for the effects of dietary supplements on asthma/lung cancer risk and mortality in smokers and non-smokers.
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Antitumor activity of alantolactone in lung cancer cell lines NCI-H1299 and Anip973.
Liu, J, Yang, Z, Kong, Y, He, Y, Xu, Y, Cao, X
Journal of food biochemistry. 2019;(9):e12972
Abstract
Alantolactone is a sesquiterpene lactone extracted from Inula helenium L. plants possessing many biological activities, including anti-inflammatory, antiproliferation, and antimicrobial. The inhibitory effects and the underlying mechanisms of alantolactone on lung cancer cells NCI-H1299 and Anip973 were investigated in this study. The results showed that alantolactone could decrease cell viability and induce cell apoptosis of NCI-H1299 and Anip973. After the cells were treated with alantolactone, the expression of Bcl-2 decreased, while the expression of Bax increased, the expression of MMP-9, MMP-7, and MMP-2 gradually decreased after alantolactone treatment. Furthermore, results showed that alantolactone could activate p38 MAPK pathway and suppress NF-κB pathway, which are involving in lung cancer development. These results indicated that alantolactone was a potential agent for lung cancer treatment. PRACTICAL APPLICATIONS Lung cancer is one of the most common contributors of cancer death in the world. Chemoprevention and chemotherapy with natural substances are prospective methods for lung cancer treatment. In recent years, the anti-cancer activity of various sesquiterpene lactones has attracted a great deal of interest. Alantolactone is the major active sesquiterpene lactones isolated from Inula helenium L, which is used as a medicine in ancient Romans due to wide range of pharmacological activities. The results obtained from this study revealed the inhibitory effects of alantolactone on lung cancer cells and might provide some experimental basis for prevention and treatment of lung cancer with alantolactone.
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Hydrogen bond analysis of the EGFR-ErbB3 heterodimer related to non-small cell lung cancer and drug resistance.
Ghosh, A, Yan, H
Journal of theoretical biology. 2019;:63-71
Abstract
Lung cancer is the predominant cause of cancer deaths on a worldwide scale. A mutation in the epidermal growth factor receptor (EGFR) can cause non-small cell lung cancer (NSCLC). The L858R one-point mutation in exon 21 in EGFR is the most prevalent in NSCLC. For over 60% of EGFR-muted NSCLC, another mutation T790M can cause drug resistance. In this paper, we consider EGFR and ErbB3 heterodimers involving three structures of EGFR, wild-type, with L858R mutation, and with L858R and T790M mutations. We perform molecular dynamics (MD) simulations to analyze hydrogen bonds in all three instances. The hydrogen bonds contribute to the conformational stability of the protein and molecular recognition. Several other parameters are also investigated in the present study, which reveals significant changes in the dimer at different levels of mutation. The knowledge and results obtained from this study lead to useful insight into the mechanism of NSCLC drug resistance.
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Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication.
Monaco, F, Gaetani, S, Alessandrini, F, Tagliabracci, A, Bracci, M, Valentino, M, Neuzil, J, Amati, M, Bovenzi, M, Tomasetti, M, et al
Cancer letters. 2019;:27-36
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Abstract
MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR-126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.
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Acquired haemophilia A in a patient with breast cancer and lung carcinoma: a case report and literature review.
Biesheuvel, V, Hiddema, SM, Levenga, H, Eikenboom, J, van der Deure, WM
The Netherlands journal of medicine. 2019;(4):153-155
Abstract
Acquired haemophilia A is a rare disorder caused by spontaneous formation of auto-antibodies (inhibitors) against coagulation factor VIII. This can lead tolife-threatening haemorrhages. Six to twenty-two percent of patients with acquired haemophilia have an underlying malignancy. We describe a 69-year-old woman with metastatic breast cancer and non-small cell lung carcinoma who presented at the emergency room with spontaneous bruising, and who was using a vitamin K antagonist. She had a prolonged activated partial thromboplastin time (aPTT) due to a coagulation factor VIII deficiency caused by factor VIII antibodies. She was treated with prednisone and cyclophosphamide.
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Fluorine 18-FDG PET/CT and Diffusion-weighted MRI for Malignant versus Benign Pulmonary Lesions: A Meta-Analysis.
Basso Dias, A, Zanon, M, Altmayer, S, Sartori Pacini, G, Henz Concatto, N, Watte, G, Garcez, A, Mohammed, TL, Verma, N, Medeiros, T, et al
Radiology. 2019;(2):525-534
Abstract
Purpose To perform a meta-analysis of the literature to compare the diagnostic performance of fluorine 18 fluorodeoxyglucose PET/CT and diffusion-weighted (DW) MRI in the differentiation of malignant and benign pulmonary nodules and masses. Materials and Methods Published English-language studies on the diagnostic accuracy of PET/CT and/or DW MRI in the characterization of pulmonary lesions were searched in relevant databases through December 2017. The primary focus was on studies in which joint DW MRI and PET/CT were performed in the entire study population, to reduce interstudy heterogeneity. For DW MRI, lesion-to-spinal cord signal intensity ratio and apparent diffusion coefficient were evaluated; for PET/CT, maximum standard uptake value was evaluated. The pooled sensitivities, specificities, diagnostic odds ratios, and areas under the receiver operating characteristic curve (AUCs) for PET/CT and DW MRI were determined along with 95% confidence intervals (CIs). Results Thirty-seven studies met the inclusion criteria, with a total of 4224 participants and 4463 lesions (3090 malignant lesions [69.2%]). In the primary analysis of joint DW MRI and PET/CT studies (n = 6), DW MRI had a pooled sensitivity and specificity of 83% (95% CI: 75%, 89%) and 91% (95% CI: 80%, 96%), respectively, compared with 78% (95% CI: 70%, 84%) (P = .01 vs DW MRI) and 81% (95% CI: 72%, 88%) (P = .056 vs DW MRI) for PET/CT. DW MRI yielded an AUC of 0.93 (95% CI: 0.90, 0.95), versus 0.86 (95% CI: 0.83, 0.89) for PET/CT (P = .001). The diagnostic odds ratio of DW MRI (50 [95% CI: 19, 132]) was superior to that of PET/CT (15 [95% CI: 7, 32]) (P = .006). Conclusion The diagnostic performance of diffusion-weighted MRI is comparable or superior to that of fluorine 18 fluorodeoxyglucose PET/CT in the differentiation of malignant and benign pulmonary lesions. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Schiebler in this issue.