Amity Institute of Pharmacy, Amity University, Noida 201313, Uttar Pradesh, India.
Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India.
Molecules. 2022 Aug 11;27(16):5104. doi: 10.3390/molecules27165104.
An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them. Three reference drugs for HCC (sorafenib, regorafenib, and nivolumab) were also examined for comparison. The in silico studies revealed that, out of the ten compounds, three of them-., -guggulsterone, dehydrocostus lactone and crocin-showed good binding efficiency with the HCC and ER stress proteins. Comparison of binding affinity with standard drugs was followed by preliminary in vitro screening of these selected compounds in human liver cancer cell lines. The results provided the basis for selecting -guggulsterone as the best-acting phytoconstituent amongst the 10 studied. Further validation of the binding efficiency of -guggulsterone was undertaking using molecular dynamics (MD) simulation studies. The effects of -guggulsterone on clone formation and cell cycle progression were also assessed. The anti-oxidant potential of -guggulsterone was analyzed through DPPH and FRAP assays. qRTPCR was utilized to check the results at the in vitro level. These results indicate that -guggulsterone should be considered as the main constituent of DuK instead of the crocin in saffron, as previously hypothesized.
一种古老的藏红花基复方草药制剂，Dawa-ul-Kurkum（DuK），已被用于治疗肝脏疾病和其他疾病，最近我们的研究团队评估了其对肝细胞癌（HCC）的抗癌潜力。为了更深入地了解 DuK 的先导分子，我们选择了其七种草药成分中的十种活性成分（藏红花酸、藏红花酸、藏红花醛、莪术酮、异戊酸、肉桂醛、对香豆酸、柠檬醛、古柯甾酮和去氢木香内酯）。我们将它们与在 HCC 的发生、发展和抑制中起重要作用的 32 种重要蛋白以及内质网（ER）应激相关蛋白进行对接，以确定它们之间的结合相互作用。还检查了三种用于 HCC 的参考药物（索拉非尼、regorafenib 和 nivolumab）进行比较。计算机研究表明，在这 10 种化合物中，有 3 种，即古柯甾酮、去氢木香内酯和藏红花酸，与 HCC 和 ER 应激蛋白具有良好的结合效率。随后比较了与标准药物的结合亲和力，并对这些选定的化合物在人肝癌细胞系中的初步体外筛选。这些结果为选择 10 种研究化合物中结合效率最好的 -guggulsterone 提供了依据。进一步通过分子动力学（MD）模拟研究验证 -guggulsterone 的结合效率。还评估了 -guggulsterone 对克隆形成和细胞周期进展的影响。通过 DPPH 和 FRAP 测定分析了 -guggulsterone 的抗氧化潜力。qRTPCR 用于检查体外水平的结果。这些结果表明，-guggulsterone 应该被视为 DuK 的主要成分，而不是以前假设的藏红花中的藏红花酸。
