Ganoderma lucidum extract attenuates the proliferation of hepatic stellate cells by blocking the PDGF receptor

Abstract

Hepatic fibrosis is an outcome of chronic liver diseases. The activation and proliferation of hepatic stellate cells (HSCs) is a key event in liver injury. The fruiting body of Ganoderma lucidum has long been a popular oriental medicine for treating liver diseases. The aim of this present study was to investigate the antiproliferative effects of the triterpenoid-rich extract (GLT) of G. lucidum in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor (PDGF)-BB. DNA synthesis was investigated by bromodeoxyuridine (BrdU) incorporation. Flow cytometry using propidium iodide (PI) labeling was carried out to analyse the cell cycle distribution and apoptosis. alpha-Smooth muscle actin (alpha-SMA) was used to evaluate extracellular matrix deposition, and western blotting was performed to measure cyclins D1 and D2, and phosphorylation of the PDGFbeta-receptor (PDGFbetaR), Akt and JNK. The results indicated that the GLT attenuated BrdU incorporation in a concentration-dependent manner with an IC(50) of 8.52 +/- 0.33 microg/mL. The inhibitory effect of the GLT was associated with downregulation of cyclins D1 and D2, and PDGFbetaR and Akt phosphorylation, upregulation of JNK phosphorylation, and a reduction in alpha-SMA expression. These results indicated that G. lucidum inhibits PDGF-BB-activated HSC proliferation possibly through blocking PDGFbetaR phosphorylation, thereby indicating its efficacy for preventing and treating hepatic fibrosis.

New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis

“…Similar to the mechanism above, in the present study, sorafenib is capable of inhibiting cellular proliferation activated by PDGF-BB in a dose-dependent manner in both cell lines. Suppression of proliferation and induction of apoptosis are accompanied by a downregulation of Cyclins and Cdks [19,28]. We also found that sorafenib caused T6 and LX2 cells to undergo arrested growth in the S phase of the cell cycle.…”

“…Rat T6 and human LX2 are well-characterized HSC lines that recapitulate many features of the activated HSC phenotype, including the expression of the PDGFR-b subunit [18,19]. HSCs were cultured in DMEM supplemented with 10% FBS.…”

Pharmacokinetics of Ganoderic Acids A and F after Oral Administration of Ling Zhi Preparation in Healthy Male Volunteers

“…One of the potent biologically active compounds that has been shown to possess diverse and potentially significant pharmacological activities is the bitter triterpenes [2]. Since the first discovery of ganoderic acids A and B, more than 150 types of triterpenes have been isolated from various parts of Ling Zhi [2, 3], among which ganoderic acids A and F (Figure 1) have received considerable attention due to their conspicuous pharmacological properties for example, antihypertensive [4], antinociceptive [5], antioxidative [6], farnesyl protein transferase inhibitory [7], and hepatoprotective activities [8, 9], especially anticancer activity [10–13] which is the most attractive character of this medicinal mushroom. Ganoderic acid A has been reported to suppress growth and invasion of highly invasive human breast cancer cells via downregulation of expression of cyclin-dependent kinase 4 that regulates cell cycle G 1 phase progression, and via suppression of secretion of urokinase-type plasminogen activator that implicates in tumor cell invasion and metastasis [12].…”

Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors

“…On the other hand, several other naturally occurring triterpenoids have demonstrated anti-platelet aggregation activity [21-24] possibly through down-regulation of phosphorylated ERK [23]. In hepatocellular stellate cells, triterpenoid appears to decrease phosphorylation of PDGF-R and AKT [25]. To the best of our knowledge, there are no reports of other synthetic triterpenoids or CDDO derivatives describing an association with increased clotting susceptibility.…”