Butyrolactone I is an ATP competitive inhibitor of cyclin-dependent kinase 1 (CDK1) with oral activity (the IC50 value of cdc2 kinase in PC-14 cells was 20μg/ml) [1]. CDK is a serine/threonine kinase that forms a complex with cyclins and plays a crucial role in controlling cell division and regulating transcription in response to extracellular and intracellular stimuli [2]. Butyrolactone I has anti-inflammatory, intestinal protection, and anti-tumor effects and can be used in the research of various cancers and non-alcoholic steatohepatitis (NASH) [3-4].
In vitro, pretreatment with Butyrolactone I (10, 20, and 50μM; 24h) can increase the cell proliferation rate of IPEC-J2 cells under heat stress in a dose-dependent manner, and alleviate cell apoptosis by regulating the ROS/PERK/CHOP signaling pathway [5]. Butyrolactone I (63-1000μM; 2h) treatment induces changes in the morphology and spores of A. terreus, increases fungal hyphal branching, reduces the average hyphal growth unit, and enhances the production of secondary metabolites [6].
In vivo, Butyrolactone I (1 and 5mg/kg/day; 14 days) orally administered increased the body weight and colon length of heat-stressed mice, significantly reduced the protein expression of Bax/Bcl-2, and alleviated intestinal oxidative stress and endoplasmic reticulum stress [5]. Butyrolactone I (10-40mg/kg; 8 weeks) orally administered reduced the serum transaminase levels of NASH mice, reduced liver fat accumulation, inhibited inflammation, alleviated oxidative stress, and improved liver fibrosis. Butyrolactone I partially alleviates NASH by inhibiting the NF-κB pathway in signal transduction [7].
References:
[1] Nishio, K., Arioka, H., Kurokawa, H., et al. Antitumor effects of butyrolactone I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines. Anticancer Res. 16(6B), 3387-3395 (1996).
[2] Wang Q, Bode A M, Zhang T. Targeting CDK1 in cancer: mechanisms and implications[J]. NPJ precision oncology, 2023, 7(1): 58.
[3] Ghfar A A, El-Metwally M M, Shaaban M, et al. Production of terretonin N and butyrolactone I by thermophilic aspergillus terreus TM8 promoted apoptosis and cell death in human prostate and ovarian cancer cells[J]. Molecules, 2021, 26(9): 2816.
[4] Chen S, Zhang Y, Niu X, et al. Coral-derived endophytic fungal product, butyrolactone-I, alleviates LPS induced intestinal epithelial cell inflammatory response through TLR4/NF-κB and MAPK signaling pathways: An in vitro and in vivo studies[J]. Frontiers in Nutrition, 2021, 8: 748118.
[5] Niu X, Chen S, Wang X, et al. Butyrolactone-I from Marine Fungal Metabolites Mitigates Heat-Stress-Induced Apoptosis in IPEC-J2 Cells and Mice Through the ROS/PERK/CHOP Signaling Pathway. Mar Drugs. 2024;22(12):564.
[6] Schimmel TG, Coffman AD, Parsons SJ. Effect of butyrolactone I on the producing fungus, Aspergillus terreus. Appl Environ Microbiol. 1998;64(10):3707-3712.
[7] Tian-Qi C, et al. Butyrolactone I attenuates inflammation in murine NASH by inhibiting the NF-κB signaling pathway. Biochem Biophys Res Commun. 2022 Oct 20;626:167-174.
Butyrolactone I是具有口服活性的由A. terreus产生的细胞周期蛋白依赖性激酶1（CDK1）的ATP竞争性抑制剂（在PC-14细胞中对cdc2 激酶的IC50值为20μg/ml）[1]。CDK是丝氨酸/苏氨酸激酶，与细胞周期蛋白形成复合物，在控制细胞分裂和调节转录以响应细胞外和细胞内刺激中起关键作用 [2]。Butyrolactone I具有抗炎、肠道保护和抗肿瘤作用，可用于各种癌症和非酒精性脂肪肝炎（NASH）的研究 [3]。
在体外，Butyrolactone I（10, 20和50µM; 24h）预处理能够以剂量依赖性方式提高热应激下IPEC-J2细胞的细胞增殖速率，并通过调节ROS/PERK/CHOP信号通路减轻细胞凋亡 [5]。Butyrolactone I（63-1000μM; 2h）处理诱导A. terreus形态和孢子发生变化，增加菌丝分支，减少平均菌丝生长单位，并增强次生代谢产物的产生 [6]。
在体内，Butyrolactone I（1和5mg/kg/day; 14 days）通过口服治疗增加了热应激小鼠的体重和结肠长度，并显著降低Bax/Bcl-2的蛋白表达，同时减轻了肠细胞中的氧化应激和内质网应激 [5]。Butyrolactone I（10-40mg/kg; 8 weeks）通过口服治疗降低了NASH小鼠的血清转氨酶水平，减少肝脏脂肪堆积、抑制炎症、减轻氧化应激，并改善肝纤维化。Butyrolactone I通过抑制信号传导中的NF-κB通路来部分缓解NASH [7]。