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

Abstract

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C21H28O2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized.Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta‐analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool.Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/β-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty three studies were selected for meta-analysis following the PRISMA statements. Fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment.Conclusion: This study suggested that Guggulsterone has apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.

Unveiling the therapeutic promise of natural products in alleviating drug‐induced liver injury: Present advancements and future prospects

“…Natural products and herbal antioxidants have gained the attention of researchers due to their hepatoprotective nature and efficacy in protecting against DILI (Gupta et al, 2023;Khan et al, 2023;Singh, Gupta, Sarwat, & Siddique, 2022;Singh, Khan, Akhtar, Rehman, et al, 2022). Studies have reported that natural products rich in flavonoids, polysaccharides, terpenes, triterpenes, polyphenols, and alkaloids have hepatoprotective effects against DILI (Figure 3) (Farghali et al, 2015).…”

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises

“…Various pathways may contribute to breast carcinogenesis, with overactivation of NF-κB signaling widely reported; NF-κB controls the expression of several antiapoptotic genes crucial for carcinogenesis (Pavitra et al, 2023). GS treatment of cancer cells suppresses the expression of antiapoptotic genes, NF-κB, and genes responsible for inflammation and cancer metastasis (Gupta et al, 2023). Cancer cells exposed to radiation normally activate prosurvival signaling pathways to prevent apoptotic cell death and according to the studies, ionizing radiation has been shown to stimulate NF-κB and related pathways which are vital for the survival and propagation of cancer cells (Huang & Zhou, 2020).…”

“…GS has been evaluated for toxicity using both in vitro and animal models. In vitro studies generally indicate that GS is nontoxic up to concentrations of 50 μM across various cell lines; at higher concentrations, specifically above 100 μM, it has been observed to induce apoptosis in certain cancer cell lines (Gupta et al, 2023) chronic toxicity studies in rodents have shown that long-term administration of GS at a dose of 500 mg/kg/day did not result in significant organ damage, although there were mild elevations in hepatic enzymes (Preethi et al, 2021). Studies reported that adverse effects are generally rare but can include mild gastrointestinal issues and skin rashes at high doses; there are isolated reports of elevated liver enzymes, although these findings have not been confirmed in larger clinical trials (Preethi et al, 2021).…”