Pattanayak Shakti Prasad, Bose Pritha, Sunita Priyashree, Siddique Mohd Usman Mohd, Lapenna Antonio
Division of Advanced Pharmacology, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India.
Division of Advanced Pharmacology, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India.
Biomed Pharmacother. 2018 Dec;108:297-308. doi: 10.1016/j.biopha.2018.08.145. Epub 2018 Sep 15.
Oxysterol receptors LXRs (α and β) are recently reported to be one of the novel and potential therapeutic targets in reducing cell proliferation and tumor growth in different system model. Activation of LXRs is correlated with modification of PI3K/Akt pathway. LXRs are also found to play a critical role in maintaining lipid homeostatais by regulating ABCA1, IDOL, SREBP1, LDLR and also certain lipogenic genes such as FASN and SCD1. In the present study a potential furanocoumarin, Bergapten (BeG) has been evaluated for its anticancer property on Hepatocellular Carcinoma (HCC) on LXR axis. The molecular docking analysis was carried out for BeG on LXR (α & β) using Maestro tool and compared with reference ligands. This was followed by in vitro (HepG2 cell lines) and in vivo (on NDEA induced HCC in Wistar albino rats) anticancer evaluation of BeG. The docking results revealed polar and hydrophobic interactions of BeG with LXR (α,β). The in vitro studies revealed the potential of BeG in lowering the accumulation of lipid droplets in HepG2 cells which was correlated with increase in LXR (α,β) protein expressions. Furthermore, the in vivo studies demonstrated the potential of BeG in ameliorating the cancer induced alterations in body weight, liver weight and significant restoration of the changes in mRNA and protein expressions of LXR(α,β), ABCA1, IDOL, SREBP1 and LDLR. BeG also modulated the expressions of PI3K, Akt and certain lipogenic genes like FASN and SCD1 and reduced the lipid droplets level in liver cancer cells. These results provide evidence and validates the critical role of BeG in maintaining the lipid homeostasis and justifies its anticancer potential against NDEA-induced HCC.
氧化甾醇受体LXRs（α和β）最近被报道是不同系统模型中减少细胞增殖和肿瘤生长的新型潜在治疗靶点之一。LXRs的激活与PI3K/Akt信号通路的改变相关。还发现LXRs通过调节ABCA1、IDOL、SREBP1、LDLR以及某些脂肪生成基因如FASN和SCD1在维持脂质稳态中起关键作用。在本研究中，对一种潜在的呋喃香豆素——补骨脂素（BeG）在LXR轴上对肝细胞癌（HCC）的抗癌特性进行了评估。使用Maestro工具对BeG与LXR（α和β）进行分子对接分析，并与参考配体进行比较。随后对BeG进行了体外（HepG2细胞系）和体内（在Wistar白化大鼠中由NDEA诱导的HCC）抗癌评估。对接结果揭示了BeG与LXR（α，β）的极性和疏水相互作用。体外研究表明BeG有降低HepG2细胞中脂滴积累的潜力，这与LXR（α，β）蛋白表达的增加相关。此外，体内研究证明BeG有改善癌症引起的体重、肝脏重量改变以及显著恢复LXR（α，β）、ABCA1、IDOL、SREBP1和LDLR的mRNA和蛋白表达变化的潜力。BeG还调节了PI3K、Akt以及某些脂肪生成基因如FASN和SCD1的表达，并降低了肝癌细胞中的脂滴水平。这些结果提供了证据，验证了BeG在维持脂质稳态中的关键作用，并证明了其对NDEA诱导的HCC的抗癌潜力。
