bims-meluca 2018-12-23 papers

Expert Opin Ther Targets. 2018 Dec 17.

Targeting the cell signaling pathway Keap1-Nrf2 as a therapeutic strategy for adenocarcinomas of the lung.

Bo Zhang, Zhiyuan Ma, Biqin Tan, Nengming Lin.

INTRODUCTION: Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-like factor 2 (Keap1-Nrf2) signaling plays a pivotal role in response to oxidative stress in lung cancer. Mutations in KEAP1/NFE2L2 genes always cause persistent Nrf2 activation in lung cancer cells that confers therapeutic resistance and aggressive tumorigenic activity, dictating either poor prognosis or short duration of response to chemotherapy in clinical observations. These findings suggest that modulation of Keap1-Nrf2 signaling presents to be a promising therapeutic target in adenocarcinomas of lung. Areas covered: We provide a review on the mechanisms underlying the regulation of Keap1-Nrf2 at different stages, including genetic mutations, epigenetic modifications, translational/post-translational alterations, and protein-protein interactions. Based on the current knowledge, we discuss the possibilities of intervening Keap1-Nrf2 in lung adenocarcinoma as a therapeutic target. Expert opinion: It is prevalently conceived that Keap1-Nrf2 signaling plays different roles at diverse stages of cancer: on one hand, Nrf2-deficiency are susceptible to carcinogens; on the other hand, Nrf2 activation has been proven to promote tumor growth. Although various Nrf2 or Keap1 inhibitors have been reported during the last decades, none of these inhibitors are currently under clinical studies or in clinical applications, suggesting that sole inhibition of Nrf2 might not be sufficient to suppress tumor growth. On the basis of current studies, we suggest that rational combination of Nrf2 suppression with chemical agents which cause enhanced oxidative imbalance or abnormal metabolism would be promising in the treatment of lung adenocarcinoma. This review provides an opportunity to consider Nrf2 as the 'Achilles heel' of lung adenocarcinoma with Nrf2 activation.

Keywords: Keap1; Nrf2; adenocarcinoma; lung; targets

DOI: https://doi.org/10.1080/14728222.2019.1559824

Clin Lung Cancer. 2018 Nov 29. pii: S1525-7304(18)30305-X. [Epub ahead of print]

High Receipt of Statins Reduces the Risk of Lung Cancer in Current Smokers With Hypercholesterolemia: The National Health Insurance Service-Health Screening Cohort.

Yu-Jin Kwon, Na-Young You, Jae-Woo Lee, Joungyoun Kim, Hee-Taik Kang.

BACKGROUND: The incidence and mortality of lung cancer have risen steadily with the increasing popularity of tobacco smoking. Observational studies suggest that statins, which are widely used to lower cholesterol, may prevent lung cancer; however, other studies have produced conflicting results. We investigated the effect of statin receipt on lung cancer risk in Korean men according to smoking status.
PATIENTS AND METHODS: We collected data from the 2002-2015 National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). We included a total of 16,588 men in the final analysis. We classified the participants as having high or low statin receipt or as not receiving statins. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer risk by statin receipt after adjusting for potential confounders.
RESULTS: We identified 363 patients with a new diagnosis of lung cancer from 2005 to 2015. Compared to participants who did not receive statins, high statin receipt resulted in a reduced lung cancer risk (HR = 0.64; 95% CI, 0.47, 0.85) after adjustment for confounders. Among current smokers, the fully adjusted HR for high statin receipt compared to those who did not receive statin therapy was 0.50 (95% CI, 0.32, 0.79).
CONCLUSION: High statin receipt was associated with lower risk of lung cancer in Korean men with hypercholesterolemia, especially current smokers.

Keywords: HMG-CoA reductase inhibitors; Korean men; Malignancy; Medication possesion ratio; Tobacco

DOI: https://doi.org/10.1016/j.cllc.2018.11.009

Medicine (Baltimore). 2018 Dec;97(51): e13652

Impact of metformin use on survival outcomes in non-small cell lung cancer treated with platinum.

Xin Wen-Xiu, Zheng Xiao-Wei, Ding Hai-Ying, Tong Ying-Hui, Kong Si-Si, Zhou Xiao-Fang, Ping Huang.

Preclinical evidence suggests that metformin, a widely used antidiabetic drug, may have a sensitizing effect on platinum. The purpose of this study was to evaluate the survival outcomes for non-small cell lung cancer (NSCLC) patients with type 2 diabetes mellitus (T2DM) using metformin during platinum-based chemotherapy.The clinicopathological parameters and survival data of 75 NSCLC patients with T2DM from January 2008 to December 2011 were collected and analyzed retrospectively. Patients were divided into 2 groups: metformin exposure group (n = 27) and non-metformin group (patients using other hypoglycemic agents or no drug for controlling n = 48). Univariate and multivariate analyses were performed to assess the association of metformin usage with overall survival (OS).Mean follow-up time was 58.7 months. The mean survival time was 36.74 months in the metformin group and 40.21 months in the non-metformin group. There was no significant difference in survival time between the 2 groups (P = .661). After adjusting gender, age, smoking status, tumor stage, tumor histology, and differentiation, multivariate analysis showed that metformin was not associated with the OS in NSCLC patients treated with concurrent platinum-based chemotherapy (hazard ratio: 1.071, 95% confidence interval: 0.577-1.986, P = .828).Our results indicated that metformin exposure had no significant effect on OS in NSCLC patients treated with platinum-based chemotherapy. Further studies are warranted to evaluate whether metformin could affect the survival of NSCLC patients treated with platinum-based chemotherapy.

DOI: https://doi.org/10.1097/MD.0000000000013652

Front Pharmacol. 2018 ;9 1411

ORY-1001 Suppresses Cell Growth and Induces Apoptosis in Lung Cancer Through Triggering HK2 Mediated Warburg Effect.

Zhaoliang Lu, Yanke Guo, Xiaoya Zhang, Jing Li, Leilei Li, Shuai Zhang, Changliang Shan.

ORY-1001, an inhibitor of covalent lysine (K)-specific demethylase 1A (KDM1A), has been used as a therapy for the treatment of acute leukemia. However, the underlying mechanisms of anticancer are still not fully elucidated. Here, we report that KDM1A is highly expressed in lung cancers, where it appears to drive aggressive growth. Furthermore, lung cancer patients with higher KDM1A levels have worse survival outcomes than patients with lower KDM1A levels. Interestingly, ORY-1001significantly inhibited the cell proliferation, colony formation, cell cycle, and induced apoptosis, by regulating the Warburg effect through controlling Hexokinases 2 (HK2) expression. In summary, these results indicate that ORY-1001 could inhibit the growth of lung cancer cells via regulating the Warburg effect by controlling HK2.

Keywords: Hexokinases 2; Warburg effect; cell proliferation; lung cancer; lysine (K)-specific demethylase 1A

DOI: https://doi.org/10.3389/fphar.2018.01411

Int J Radiat Biol. 2018 Dec 17. 1-23

Glutaminase Inhibitor CB-839 Increases Radiation Sensitivity of Lung Tumor Cells and Human Lung Tumor Xenografts in Mice.

Gunnar Boysen, Azemat Jamshidi-Parsian, Mary A Davis, Eric R Siegel, Rajshekhar A Kore, Ruud P M Dings, Robert J Griffin.

PURPOSE: The purpose of this study was to translate our in vitro therapy approach to an in vivo model. Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Studying lymph-node aspirates containing malignant lung tumor cells showed a strong correlation between glutamine consumption and glutathione (GSH) excretion. Subsequent experiments with A549 and H460 lung tumor cell lines provided additional evidence for glutamine's role in driving synthesis and excretion of GSH. Using stable-isotope-labeled glutamine as a tracer metabolite, we demonstrated that the glutamate group in GSH is directly derived from glutamine, linking glutamine utilization intimately to GSH syntheses.
MATERIALS AND METHODS: To understand the possible mechanistic link between glutamine consumption and GSH excretion, we studied GSH metabolism in more detail. Inhibition of glutaminase (GLS) with BPTES, a GLS-specific inhibitor, effectively abolished GSH synthesis and excretion. Since our previous work, several novel GLS inhibitors became available and we report herein effects of CB-839 in A427, H460 and A549 lung tumor cells and human lung tumor xenografts in mice.
RESULTS: Inhibition of GLS markedly reduced cell viability, producing ED50 values for inhibition of colony formation of 9, 27 and 217 nM in A427, A549 and H460, respectively. Inhibition of GLS is accompanied by ∼30% increased response to radiation, suggesting an important role of glutamine-derived GSH in protecting tumor cells against radiation-induce injury. In subsequent mouse xenografts, short-term CB-839 treatments reduced serum GSH by >50% and increased response to radiotherapy of H460-derived tumor xenografts by 30%.
CONCLUSION: The results support the proposed mechanistic link between GLS activity and glutathione synthesis and suggest that GLS inhibitors are effective radiosensitizers.

DOI: https://doi.org/10.1080/09553002.2018.1558299