Abstract
Purpose: This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and TGF-β/Smad pathways in hepatocellular carcinoma Hep-G2 cells surviving sorafenib. Methods: Hepatocellular carcinoma HepG2 cells were treated with sorafenib 10 μM. Cells surviving sorafenib treatment (HepG2surv) were then treated vehicle, sorafenib, alpha mangostin, or combination of sorafenib and alpha mangostin. Afterward, cells were observed for their morphology with an inverted microscope and counted for cell viability. The concentrations of transforming growth factor (TGF)-β1 in a culture medium were examined using ELISA. The mRNA expressions of TGF-β1, TGF-β1-receptor, Smad3, Smad7, E-cadherin, and vimentin were evaluated using quantitative reverse transcriptase–polymerase chain reaction. The protein level of E-cadherin was also determined using western blot analysis. Results: Treatment of alpha mangostin and sorafenib caused a significant decrease in the viability of sorafenib-surviving HepG2 cells versus control (both groups with P <0.05). Our study found that alpha mangostin treatment increased the expressions of vimentin (P <0.001 versus control). In contrast, alpha mangostin treatment tends to decrease the expressions of Smad7 and E-cadherin (both with P >0.05). In line with our findings, the expressions of TGF-β1 and Smad3 are significantly upregulated after alpha mangostin administration (both with P <0.05) versus control. Conclusion: Alpha mangostin reduced cell viability of sorafenib-surviving HepG2 cells; however, it also enhanced epithelial–mesenchymal transition markers by activating TGF-β/Smad pathways.
Highlights
Hepatocellular carcinoma (HCC) is the second deadliest cancer and the fifth most common cancer worldwide
This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and transforming growth factor (TGF)-β/Smad pathways in hepatocellular carcinoma Hep-G2 cells surviving sorafenib
The previous study has proved the antiproliferative potential of alpha mangostin by G1/S cycle arrest, apoptosis mediated by caspase-independent pathways, and topoisomerase inhibition.[12,18,22]
Summary
Hepatocellular carcinoma (HCC) is the second deadliest cancer and the fifth most common cancer worldwide. Primary treatment choices for HCC are surgical operation and hepatic transplantation. Because of late diagnosis, most patients were unsuitable to receive those treatments. Most patients with HCC are often found at an advanced stage, which can be treated with sorafenib, the first-line approved treatment by the FDA. Sorafenib works as antiproliferation and antiangiogenesis by inhibiting several members of multikinase signaling pathways C-rapidly accelerated fibrosarcoma (C-RAF) and B-RAF and blocking proangiogenic kinases such as vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-3), platelet-derived growth factors (PDGFs) receptor, c-Kit, and fims-like tyrosine kinase. Drug resistance leads to treatment failure and, the poor prognosis of the patient. Molecular mechanisms underlying drug resistance are poorly understood. Molecular mechanisms underlying drug resistance are poorly understood. 1–5
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