Background
SR9009 is a synthetic REV-ERB agonist used for treatment with metabolic diseases such as obesity, bipolar, anxiety and depressive disorders.[1]
In vitro experiment it demonstrated that treatment with 10μM of SR9009 induced obvious apoptosis in SCLC cells.[1] In vitro, treatment with 0?μM, 2.5?μM, 5?μM, or 10?μM of SR9009 cardiomyocytes showed no difference in hypoxia-induced cell death versus vehicle-treated controls. SR9009 treatment also did not significantly rescue cardiomyocyte cell death under any conditions.[2] Treatment with 10 μM of SR9009 for 2 days reduced the viability of wild-type mESCs in a dose-dependent manner. And SR9009 also had strong metabolic effects on mESC mitochondria, decreasing both their stimulated and basal.[3] SR9009 had a cytotoxic effect on tumor cells from brain, leukemia, breast, colon and melanoma at the 20 μM concentrations.[5]
In vivo, LPS-induced sepsis mice were treated with 50 mg/kg SR9009, the pathological lesions such as hemorrhage and edema in the lung tissue and the infiltration of inflammatory cells was obviously decreased.[4] In vivo efficacy study it shown that treatment with 100 mg/kg of SR9009 orally reduced weight gain as well as less severe hyperlipidemia and hepatic steatosis as compared to the control group. However, SR9009 gavage had no effect on the expression of lipogenic genes in the liver, TAG synthesis genes in the WAT, and genes involved in fatty acid oxidation in the skeletal muscle. [6]
参考文献:
[1]. Shen W, et al. SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy. Theranostics. 2020 Mar 15;10(10):4466-4480.
[2]. Reitz CJ, et al. SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome. Commun Biol. 2019 Oct 3;2:353.
[3]. Dierickx P, et al. SR9009 has REV-ERB-independent effects on cell proliferation and metabolism. Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12147-12152.
[4]. Griffin P, et al. Circadian clock protein Rev-erbα regulates neuroinflammation. Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5102-5107.
[5]. Sulli G, et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 2018 Jan 18;553(7688):351-355.
[6]. Yu F, et al. Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding. Nat Commun. 2021 Sep 7;12(1):5323.
SR9009 是一种合成的 REV-ERB 激动剂，用于治疗肥胖、躁郁症、焦虑症和抑郁症等代谢性疾病。[1]
体外实验表明，10μM SR9009 可明显诱导 SCLC 细胞凋亡。[1] 体外，0μM、2.5μM、5μM 或 10μM SR9009心肌细胞在缺氧诱导的细胞死亡与载体处理的对照中没有差异。在任何条件下，SR9009 处理也没有显着挽救心肌细胞死亡。[2]用 10 μM SR9009 处理 2 天以剂量依赖性方式降低野生型 mESC 的活力。并且 SR9009 对 mESC 线粒体也有很强的代谢作用，降低它们的刺激线粒体和基础线粒体。[3] SR9009 在 20 μM 时对来自脑、白血病、乳腺癌、结肠癌和黑色素瘤的肿瘤细胞具有细胞毒性作用浓度。[5]
在体内，LPS诱导的脓毒症小鼠经50 mg/kg SR9009处理后，肺组织出血、水肿、炎症细胞浸润等病理病变明显减少。[4] 体内功效研究表明，与对照组相比，口服 100 mg/kg SR9009 的治疗减少了体重增加以及较轻的高脂血症和肝脂肪变性。然而，SR9009 灌胃对肝脏中的脂肪生成基因、WAT 中的 TAG 合成基因和骨骼肌中参与脂肪酸氧化的基因的表达没有影响。 [6]
Protocol
| Cell experiment [1]: |
|
Cell lines
|
HepG2 cells
|
|
Preparation Method
|
5?×?103 HepG2 cells were allowed to attach overnight at 37°C in a 96-well plate. Cultured cells were incubated with DMSO (vehicle) or REV-ERB agonist (SR9009) at different concentrations (5, 10, 20, and 40?μM) for 96?h. Then, cell viability was analyzed by MTT assay considering vehicle-treated cells (DMSO) as 100% of viability.
|
|
Reaction Conditions
|
5, 10, 20, and 40?μM; 96?h
|
|
Applications
|
SR9009 significant effects on cell morphology and reduction in cell viability were observed at final concentrations of 20 and 40?μM for 48 and 72?h.
|
| Animal experiment [2]: |
|
Animal models
|
BALB/c nude mice
|
|
Preparation Method
|
SCLC cells were harvested and suspended in culture medium, and 1 × 107 cells were subcutaneously injected to establish the SCLC xenograft model. When tumors reached an average size of 100 mm3, mice were randomly divided into four groups. Then, SR9009 (50 mg/kg) was administered intraperitoneally once every two days. Mice were intraperitoneally injected with physiological saline containing chemotherapeutics or physiological saline alone as a control.
|
|
Dosage form
|
50 mg/kg; i.p.
|
|
Applications
|
SR9009 treatment led to marked tumor growth inhibition in both the chemosensitive and chemoresistant tumor models.
|
|
参考文献:
[1]. Wagner PM, et al. Chemotherapeutic Effect of SR9009, a REV-ERB Agonist, on the Human Glioblastoma T98G Cells. ASN Neuro. 2019 Jan-Dec;11:1759091419892713.
[2]. Shen W, et al. SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy. Theranostics. 2020 Mar 15;10(10):4466-4480.
|
没有评价数据