bims-meluca 2022-01-02 papers

Biomed Pharmacother. 2021 Dec 23. pii: S0753-3322(21)01333-0. [Epub ahead of print]146 112546

Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells.

Shibo Sun, Yue Zhang, Weiping Xu, Rui Yang, Yijia Yang, Jianli Guo, Qiang Ma, Kun Ma, Jie Zhang, Jianqiang Xu.

Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells.

Keywords: Glucose limitation; KEAP1 mutation; Naphthoquinone; Non-small cell lung cancer (NSCLC); Plumbagin; Thioredoxin reductase 1

DOI: https://doi.org/10.1016/j.biopha.2021.112546

Oxid Med Cell Longev. 2021 ;2021 9259297

Comprehensive Analysis of Alteration Landscape and Its Clinical Significance of Mitochondrial Energy Metabolism Pathway-Related Genes in Lung Cancers.

Zhen Ye, Huanhuan Zhang, Fanhua Kong, Jing Lan, Shuying Yi, Wenshuang Jia, Shu Zheng, Yuna Guo, Xianquan Zhan.

Background: Mitochondria are the energy factories of cells. The abnormality of mitochondrial energy metabolism pathways is closely related to the occurrence and development of lung cancer. The abnormal genes in mitochondrial energy metabolism pathways might be the novel targets and biomarkers to diagnose and treat lung cancers.
Method: Genes in major mitochondrial energy metabolism pathways were obtained from the KEGG database. The transcriptomic, mutation, and clinical data of lung cancers were obtained from The Cancer Genome Atlas (TCGA) database. Genes and clinical biomarkers were mined that affected lung cancer survival. Gene enrichment analysis was performed with ClusterProfiler and the gene set enrichment analysis (GSEA). STRING database and Cytoscape were used for protein-protein interaction (PPI) analysis. The diagnostic biomarker pattern of lung cancer was optimized, and its accuracy was verified with 10-fold cross-validation. The four genes screened by logistic regression model were verified by western blot in 5 pairs of lung cancer specimens collected in hospital.
Results: In total, 188 mitochondrial energy metabolism pathway-related genes (MMRGs) were included in this study. GSEA analysis found that MMRGs in the lung cancer group were mainly enriched in the metabolic pathway of oxidative phosphorylation and electron respiratory transport chain compared to the control group. Age did not affect the mutation frequency of MMRGs. Comparative analysis of these 188 MMRGs identified 43 differentially expressed MMRGs (24 upregulated and 19 downregulated) in the lung cancer group compared to the control group. The survival analysis of these 43 differentially expressed MMRGs found that the survival time was better in the low-expressed GAPDHS group than that in the high-expressed GAPDHS group of lung cancers. The advanced age, high expression of GAPDHS, low expressions of ACSBG1 and CYP4A11, and ACOX3 mutation were biomarkers of poor prognosis in lung cancers. PPI analysis showed that proteins such as GAPDH and GAPDHS interacted with many proteins in mitochondrial metabolic pathways. A four-MMRG-signature model (y = 0.0069∗ACADL - 0.001∗ALDH18A1 - 0.0405∗CPT1B + 0.0008∗PPARG - 1.625) was established to diagnose lung cancer with the accuracy up to 98.74%, AUC value up to 0.992, and a missed diagnosis rate of only 0.6%. Western blotting showed that ALDH18A1 and CPT1B proteins were significantly overexpressed in the lung cancer group (p < 0.05), and ACADL and PPARG proteins were slightly underexpressed in the lung cancer group (p < 0.05), which were consistent with the results of their corresponding mRNA expressions.
Conclusion: Mitochondrial energy metabolism pathway alterations are the important hallmarks of lung cancer. Age did not increase the risk of MMRG mutation. High expression of GAPDHS, low expression of ACSBG1, low expression of CYP4A11, mutated ACOX3, and old age predict a poor prognosis of lung cancer. Four differentially expressed MMRGs (ACADL, ALDH18A1, CPT1B, and PPARG) established a logistic regression model, which could effectively diagnose lung cancer. At the protein level, ALDH18A1 and CPT1B were significantly upregulated, and ACADL and PPARG were slightly underexpressed, in the lung cancer group compared to the control group, which were consistent with the results of their corresponding mRNA expressions.

DOI: https://doi.org/10.1155/2021/9259297

Respir Investig. 2021 Dec 28. pii: S2212-5345(21)00191-X. [Epub ahead of print]

Correlation between body mass index and efficacy of anti-PD-1 inhibitor in patients with non-small cell lung cancer.

Akiko Tateishi, Hidehito Horinouchi, Tatsuya Yoshida, Ken Masuda, Hitomi Jo, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Noboru Yamamoto, Yuichiro Ohe.

BACKGROUND: High body mass index (BMI) has been reported to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC), but the association between BMI and efficacy of anti-PD-1 inhibitors remains controversial. The present study investigated this association in patients with advanced NSCLC.
METHODS: We retrospectively reviewed patients with advanced NSCLC who received PD-1 inhibitors at the National Cancer Center Hospital between January 2016 and December 2018. The efficacy of PD-1 inhibitors (progression-free survival [PFS], overall survival [OS], and response rate) was compared between overweight (BMI ≥25 kg/m2) and non-overweight (BMI <25 kg/m2) groups. Cohort 1 included patients with high PD-L1 expression who were treated with pembrolizumab as first-line therapy; Cohort 2 included patients treated with nivolumab/pembrolizumab as second- or later-line treatment.
RESULTS: A total of 324 patients were included in this study and the median BMI (IQR) was 21.4 (19.5-23.6) kg/m2. Of the 324 patients, 279 (86.1%) and 45 (13.9%) were in the non-overweight and overweight groups, respectively. No significant differences in objective response rate (ORR), PFS, or OS were found between overweight and non-overweight patients overall (n = 324; overweight vs. non-overweight: ORR, 28.9% vs. 31.9%, respectively [p = 0.68]; PFS, 7.6 vs. 5.8 months, respectively [p = 0.43]; and OS, 17.6 vs. 15.3 months, respectively [p = 0.90]), or between overweight and non-overweight patients in Cohorts 1 and 2.
CONCLUSIONS: No significant differences in the efficacy of PD-1 inhibitors were observed between overweight and non-overweight patients.

Keywords: Anti-PD-1 inhibitor; Body mass index; Immune-checkpoint inhibitor; Non-overweight; Overweight

DOI: https://doi.org/10.1016/j.resinv.2021.11.003

JPEN J Parenter Enteral Nutr. 2021 Dec 27.

The value of the controlling nutritional status score in predicting the prognosis of patients with lung cancer: A multicenter, retrospective study.

Xiao-Yue Liu, Xi Zhang, Qi Zhang, Hai-Lun Xie, Guo-Tian Ruan, Tong Liu, Meng-Meng Song, Yi-Zhong Ge, Hong-Xia Xu, Chun-Hua Song, Han-Ping Shi.

BACKGROUND: The body's immune-nutritional status affects prognosis in patients with lung cancer. The Controlling Nutritional Status (CONUT) score is an immune-nutrition-related index associated with prognosis in other tumors. We aimed to assess the value of CONUT in predicting prognosis in patients with lung cancer.
METHODS: In this retrospective multicenter study, 1,339 patients with lung cancer were divided into low- and high-CONUT score groups. The relationship between CONUT scores and overall survival (OS) was assessed by survival curves and Cox's proportional hazards regression modelling. A nomogram including CONUT and other clinical variables was established.
RESULTS: There were 659 (49.2%; mean age 59.91 years) low- and 680 (50.8%; mean age 62.23 years) high-CONUT score patients. OS was significantly worse in patients with high than in those with low CONUT scores (P < 0.001), even after stratification by pathological types (non-small-cell lung cancer and small-cell lung cancer) and Tumor-Node-Metastasis (TNM) stages. A high CONUT score independently predicted risk in patients with lung cancer (adjusted hazard ratio: 1.48, 95% confidence interval: 1.26-1.73; P < 0.001). The CONUT-based nomogram could predict prognosis well (C-index: 0.701), with better resolution and accuracy than TNM staging for predicting OS at 1, 2, and 3 years (Area under the ROC curve: 0.735 vs. 0.678; 0.742 vs. 0.696; and 0.768 vs. 0.743).
CONCLUSION: The CONUT score can predict prognosis in patients with lung cancer. A CONUT-based nomogram can improve the accuracy of survival prediction in such patients. This article is protected by copyright. All rights reserved.

Keywords: CONUT score; immune-nutrition; inflammation; lung cancer; overall survival; prognosis

DOI: https://doi.org/10.1002/jpen.2321