bims-meluca 2021-09-05 papers

Pharmacol Res Perspect. 2021 Oct;9(5): e00854

EVT-701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti-tumor activity in models of solid cancers.

Raquel Luna Yolba, Virgile Visentin, Caroline Hervé, Johanna Chiche, Jean-Ehrland Ricci, Jérôme Méneyrol, Michaël R Paillasse, Nathalie Alet.

Targeting the first protein complex of the mitochondrial electron transport chain (MC1) in cancer has become an attractive therapeutic approach in the recent years, given the metabolic vulnerabilities of cancer cells. The anticancer effect exerted by the pleiotropic drug metformin and the associated reduction in hypoxia-inducible factor 1α (HIF-1α) levels putatively mediated by MC1 inhibition led to the development of HIF-1α inhibitors, such as BAY87-2243, with a more specific MC1 targeting. However, the development of BAY87-2243 was stopped early in phase 1 due to dose-independent emesis and thus there is still no clinical proof of concept for the approach. Given the importance of mitochondrial metabolism during cancer progression, there is still a strong therapeutic need to develop specific and safe MC1 inhibitors. We recently reported the synthesis of compounds with a novel chemotype and potent action on HIF-1α degradation and MC1 inhibition. We describe here the selectivity, safety profile and anti-cancer activity in solid tumors of lead compound EVT-701. In addition, using murine models of lung cancer and of Non-Hodgkin's B cell lymphoma we demonstrated that EVT-701 reduced tumor growth and lymph node invasion when used as a single agent therapy. LKB1 deficiency in lung cancer was identified as a potential indicator of accrued sensitivity to EVT-701, allowing stratification and selection of patients in clinical trials. Altogether these results support further evaluation of EVT-701 alone or in combination in preclinical models and eventually in patients.

Keywords: DLBCL; LKB1; Non-Hodgkin's lymphoma; STK11; lung cancer; mitochondrial complex 1

DOI: https://doi.org/10.1002/prp2.854

Signal Transduct Target Ther. 2021 Sep 01. 6(1): 330

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development.

Ming Li, Bingjie Hao, Menghuan Zhang, Russel J Reiter, Shumeng Lin, Tiansheng Zheng, Xiangyun Chen, Yanbei Ren, Liduo Yue, Baigenzhin Abay, Guojie Chen, Xiao Xu, Yufeng Shi, Lihong Fan.

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .

DOI: https://doi.org/10.1038/s41392-021-00745-7

World J Surg Oncol. 2021 Sep 01. 19(1): 262

The expression of miRNA-216b is negatively correlated with 18F-FDG uptake in non-small cell lung cancer.

Mingfei Zuo, Lan Yao, Lijuan Wen, Jianfei Shen, Na Zhang, Tian Bai, Qicheng Huang.

BACKGROUND: This study aimed to investigate the correlation between miRNA-216b expression in patients with non-small cell lung cancer (NSCLC) and 18F-fluorodeoxyglucose (FDG) uptake by PET/CT and to explore the clinical application value of 18F-FDG PET/CT in miRNA-216b based on therapy for NSCLC.
METHODS: Eighty patients with NSCLC and 40 healthy subjects were enrolled in our study. The SUVmax of the lesion area by PET/CT imaging was calculated. SUVmax represented the highest concentration of 18F-FDG in the lesion. The expression of miRNA-216b in the plasma and fiber bronchoscopic puncture of NSCLC patients was detected by RT qPCR. Then Pearson correlation analysis was used to analyze the correlation between miRNA-216b expression and 18F-FDG uptake in patients with different types of NSCLC.
RESULTS: Compared with healthy subjects, SUVmax of early adenocarcinoma and advanced adenocarcinoma were increased. Compared with healthy subjects, SUVmax of early squamous and advanced squamous were increased. And the SUVmax content of advanced adenocarcinoma and squamous cell carcinoma was higher than that of early adenocarcinoma and squamous cell carcinoma. Compared with healthy subjects, the expression of miRNA-216b in the plasma of patients with early and advanced adenocarcinoma was reduced, and the expression of miRNA-216b in the plasma of patients with early and advanced squamous cell carcinoma was reduced. Compared with adjacent tissues, the expression of miRNA-216b in early adenocarcinoma tissues and advanced adenocarcinoma tissues was reduced, and the expression in early squamous cell carcinoma and advanced squamous cell carcinoma was reduced. Pearson correlation analysis showed a negative correlation between SUVmax and miRNA-216b (plasma and tissue) in patients with four types of NSCLC.
CONCLUSION: miRNA-216b expression was negatively correlated with 18F-FDG uptake in NSCLC. miRNA-216b could be used for the classification and staging of non-small cell lung cancer. 18F-FDG PET/CT may be used to evaluate the therapeutic response in application of miRNA-216b-based cancer treatment.

Keywords: Adenocarcinoma; Non-small cell lung cancer; PET/CT; Squamous cell carcinoma; miRNA-216

DOI: https://doi.org/10.1186/s12957-021-02376-2

J Cancer. 2021 ;12(19): 5888-5894

Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis.

Yuanyuan Zeng, Jie Zhang, Mengmeng Xu, Fuxian Chen, Ruidong Zi, Jicheng Yue, Yanan Zhang, Nannan Chen, Y Eugene Chin.

In the last few years, cellular metabolic reprogramming has been acknowledged as a hallmark of human cancer and evaluated for its crucial role in supporting the proliferation and survival of human cancer cells. In a variety of human tumours, including hepatocellular carcinoma (HCC), breast cancer and non-small-cell lung cancer (NSCLC), a large amount of carbon is reused in serine/glycine biosynthesis, accompanied by higher expression of the key glycine synthetic enzyme mitochondrial serine hydroxymethyltransferase 2 (SHMT2). This enzyme can convert serine into glycine and a tetrahydrofolate-bound one-carbon unit, ultimately supporting thymidine synthesis and purine synthesis and promoting tumour growth. In tumour samples, elevated expression of SHMT2 was found to be associated with poor prognosis. In this review, the pivotal roles of SHMT2 in human carcinogenesis are described, highlighting the underlying regulatory mechanisms through promotion of tumour progression. In conclusion, SHMT2 may serve as a prognostic marker and a target for anticancer therapies.

Keywords: Serine hydroxymethyltransferase 2 (SHMT2); cell proliferation; human carcinogenesis; predictive biomarker; tumour growth

DOI: https://doi.org/10.7150/jca.60170