Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma

Li, Xinyan; Yang, Xiaoqin; Chen, Xinmei; Zhang, Yantao; Pan, Xuebin; Wang, Guiping; Ye, Yun

doi:10.7150/jca.12191

Cited by 13 publications

(5 citation statements)

References 29 publications

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“…A few previous studies have used gene set enrichment analysis to connect disease signatures with drug signatures and identified candidate drugs for cancer, neurological, and gastrointestinal disorders, as suggested by subsequent effect studies in cell lines and animal models (3)(4)(5)(6). However, it remains to be shown whether such signature connections can be used to identify compounds with pathophysiological relevance for humans.…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

Axelsson

Tubbs

Mecham³

et al. 2017

Sci. Transl. Med.

265

175

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A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature. Sulforaphane suppressed glucose production from hepatic cells by nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and decreased expression of key enzymes in gluconeogenesis. Moreover, sulforaphane reversed the disease signature in the livers from diabetic animals and attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin. Finally, sulforaphane, provided as concentrated broccoli sprout extract, reduced fasting blood glucose and glycated hemoglobin (HbA1c) in obese patients with dysregulated type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

Axelsson

Tubbs

Mecham³

et al. 2017

Sci. Transl. Med.

265

175

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“…Bezafibrate, as an agonist of PGC-1α/PPAR complexes, has showed synergistic tumor-suppression activity with anti-PD-L1 monoclonal antibody (mAb) in mouse colon xenograft models. 8,9 However, although Liu et al 10 has found bezafibrate may be a potential therapeutic drug for lung adenocarcinoma (AC) by targeting cyclin-dependent kinase 2 (CDK2) to induce cell cycle arrest in lung (AC) cells, there is rare report of bezafibrate in regulating the function of T cells, let alone enhancing the antitumor effect of PD-1 blockade in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

Wan

Zhu

et al. 2019

Tumori

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Purpose: The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells–derived in vivo tumor model, using bezafibrate. Methods: Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction. Results: The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)–related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate. Conclusions: Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.

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“…In order to improve the prognosis of patients with glioma, we used CMap to obtain four small molecule compounds with potential therapeutic effects on glioma. Recently, a study uncovered that beza brate can serves as a drug for lung adenocarcinoma in vitro assays, in which inhibited proliferation and caused cell cycle arrest [37]. Giacinti et al revealed that scriptaid has strong antitumour activity in breast cancer cell lines [38].…”

Section: Discussionmentioning

confidence: 99%

High TROAP Expression Correlates With Shorter Survival in Patients With Glioma: A Study Based on Multiple Data Fusion Analysis

Liu

Cheng³

et al. 2021

Preprint

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Trophinin-associated protein (TROAP) was originally identified to mediate the embryo transfer process and participate in the regulation of microtubules but was later found to be associated with the biological behavior of various types of cancers. However, there is limited information about the role of TROAP in glioma. In this study, thousands of glioma samples were obtained from multiple independent datasets to detect changes in TROAP mRNA and protein expression levels in glioma, we found that compared with normal brain tissues, the expression of TROAP in glioma was significantly increased at both levels. Then, the correlations between TROAP and clinical characteristics and prognosis in glioma were revealed through a series of bioinformatics analysis methods. The overexpression of TROAP was an independent risk factor for glioma and was associated with a reduced overall survival rate of glioma patients. In addition, TROAP had value for determining the prognosis of patients, especially patients with WHO grade III glioma. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to verify the expression level of TROAP in glioma cell lines. Subsequently, GSEA identified homologous recombination, cell cycle and p53 signalling pathways as differentially enriched with the high TROAP expression phenotype. Finally, four drugs that may inhibit TROAP expression and have potential therapeutic value for glioma were screened out through CMap website: bezafibrate, clobetasol, scriptaid, and thioguanosine. In conclusion, TROAP, as a new oncogene, leads to poor prognosis of glioma patients, and as a highly specific biomarker, provides the possibility for individual clinical treatment of glioma patients.

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Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma

Cited by 13 publications

References 29 publications

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

High TROAP Expression Correlates With Shorter Survival in Patients With Glioma: A Study Based on Multiple Data Fusion Analysis

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