Z-Guggulsterone Is a Potential Lead Molecule of Dawa-ul-Kurkum against Hepatocellular Carcinoma

Abstract

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—viz., Z-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 Z-guggulsterone as the best-acting phytoconstituent amongst the 10 studied. Further validation of the binding efficiency of Z-guggulsterone was undertaking using molecular dynamics (MD) simulation studies. The effects of Z-guggulsterone on clone formation and cell cycle progression were also assessed. The anti-oxidant potential of Z-guggulsterone was analyzed through DPPH and FRAP assays. qRTPCR was utilized to check the results at the in vitro level. These results indicate that Z-guggulsterone should be considered as the main constituent of DuK instead of the crocin in saffron, as previously hypothesized.

Anti-cancer activity of guggulsterone by modulating apoptotic markers: a systematic review and meta-analysis

“…Bioactive compounds have several action mechanisms involved in the induction of cancer cell apoptosis. In tumor cells, they function via modulating the extrinsic and intrinsic pathways of apoptosis, channeling important cell signaling pathways such as mTOR-AKT, Ras/NF-κβ, ROS/JNK, JAK/STAT, and Src/Fak and regulating gene expression ( Huang et al, 2018 ; Gupta et al, 2021 ; Gupta et al, 2022a ; Gupta et al, 2022b ; Gupta et al, 2023 ). Treatment with Guggulsterone also altered the expression of different gene families which collaborate in the induction of apoptosis.…”

Pharmacological Studies on the Efficacy of Polyherbal Formulation Dawa ul kurkum in DEN-Induced 2-AAF-Promoted Hepatocellular Carcinoma in Male Wistar Rats

“…HCC is most commonly seen chronic liver disease caused by alcohol overuse, hepatitis B/C virus (HBV/HCV), or metabolic syndrome [22]. It is frequently multi-nodular when detected because of its synchronous progression.…”

Hepatoprotective Effect of Medicine Food Homology Flower Saffron against CCl4-Induced Liver Fibrosis in Mice via the Akt/HIF-1α/VEGF Signaling Pathway

“…Currently, saffron is mainly used for treating cardiovascular diseases and liver diseases in clinics. At present, there are many preparations containing saffron (Figure 1), such as Dawa UL kurkum [14], llkl [15], saffron total glycoside tablets [16], and Liuwei xihonghua koufuye, Bawei xihonghua Qingganre capsules, which are widely used in liver diseases [17]. Modern studies have found that saffron is a good anti-inflammatory, antioxidant, and anti-apoptotic agent, and has a significant liver protective effect [17][18][19][20].…”