Evaluation of pro-apoptotic potential of taxifolin against liver cancer

Abstract

Liver cancer is the second most common cause of cancer-induced deaths worldwide. Liver cirrhosis and cancer are a consequence of the abnormal angio-architecture formation of liver and formation of new blood vessels. This angiogenesis is driven by overexpression of hypoxia-inducible factor 1-alpha (Hif1-α) and vascular endothelial growth factor (VEGF). Apart from this, protein kinase B (Akt) is also impaired in liver cancer. Despite the advancement in conventional treatments, liver cancer remains largely incurable. Nowadays, the use of naturally occurring anticancer agents particularly flavonoids is subject to more attention due to their enhanced physicochemical properties. Therefore, this study underlines the use of a natural anticancer agent taxifolin in the treatment of liver cancer using hepatocellular carcinoma cell line HepG2 and Huh7. The aim of our study is to devise a natural and efficient solution for the disease prevalent in Pakistan. The study involved the assessment of binding of ligand taxifolin using molecular docking. The binding of taxifolin with the proteins (Hif1-α, VEGF and Akt) was calculated by docking using Vina and Chimera. Further evaluation was performed by cell viability assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay), colony formation assay, cell migration assay, DNA ladder assay and flow cytometry. To see whether taxifolin directly affected expression levels, analysis of gene expression of Hif1-α, VEGF and Akt was performed using real-time polymerase chain reaction (qPCR) and western blotting. In silico docking experiments revealed that these proteins showed favorable docking scores with taxifolin. Treatment with taxifolin resulted in the inhibition of the liver cancer growth and migration, and induced apoptosis in HepG2 and Huh7 cell lines at an inhibitory concentration (IC50) value of 0.15 µM and 0.22 µM, respectively. The expression of HIF1-α, VEGF and Akt was significantly reduced in a dose- dependent manner. The inhibitory effect of taxifolin on hepatic cells suggested its chemopreventive and therapeutic potential. The studied compound taxifolin exhibited pronounced pro-apoptotic and hepatoprotective potential. Our study has confirmed the pro-apoptotic potential of taxifolin in liver cancer cell lines and will pave a way to the use of taxifolin as a chemotherapeutic agent after its further validation on the animal models and humans based epidemiological studies.

An insight into novel therapeutic potentials of taxifolin

“…In vitro experiments showed that treatment with taxifolin could induce apoptosis in HepG2 and Huh7 cell lines. The potential of taxifolin in the treatment of liver cancer has been confirmed, but further verification in animal model experiments is still required ( Butt et al, 2021 ).…”

Chiral Flavonoids as Antitumor Agents

“…Docking studies showed that the hydroxyl group of taxifolin ( 14) interacts specifically with amino acids from the binding pocket of VEGF, Akt and Hif1α which are upregulated in hepatic cancer cells. The cytotoxic potential of taxifolin ( 14) was proven by the low IC 50 values in HepG2 (0.15 µM) and Huh7 cells (0.22 µM) [80].…”

“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 9 of 32 are upregulated in hepatic cancer cells. The cytotoxic potential of taxifolin ( 14) was proven by the low IC50 values in HepG2 (0.15 µM) and Huh7 cells (0.22 µM) [80]. Silibinin or silybin is the major bioactive compound isolated from the milk thistle (Silybum marianum) extract, commonly used in the Mediterranean diet.…”

Oridonin from Rabdosia rubescens: An emerging potential in cancer therapy – A comprehensive review

“…However, rising rate of cancer drug resistance has jeopardized the chemotherapeutic treatment efficacy. Therefore, efforts are being made in identifying unique molecular targets for improving diagnosis (Khan et al., 2022 ; Khan, Safi, et al., 2020 ; Shabbir et al., 2022 ), using natural compounds as chemopreventive agents, or novel therapeutic compounds for cancer management (Butt et al., 2021 ; Khan, Quispe, et al., 2020 ; Shabbir et al., 2021 ). In this regard, an ent‐kaurane diterpenoid, ORI, first isolated from the leaves of Rabdosia rubescens may serve as a lead candidate.…”