Potential Application of Gambogic Acid for Retarding Renal Cyst Progression in Polycystic Kidney Disease

Abstract

Abnormal cell proliferation and accumulation of fluid-filled cysts along the nephrons in polycystic kidney disease (PKD) could lead to a decline in renal function and eventual end-stage renal disease (ESRD). Gambogic acid (GA), a xanthone compound extracted from the brownish resin of the Garcinia hanburyi tree, exhibits various pharmacological properties, including anti-inflammation, antioxidant, anti-proliferation, and anti-cancer activity. However, its effect on inhibiting cell proliferation in PKD is still unknown. This study aimed to determine the pharmacological effects and detailed mechanisms of GA in slowing an in vitro cyst growth model of PKD. The results showed that GA (0.25–2.5 μM) significantly retarded MDCK cyst growth and cyst formation in a dose-dependent manner, without cytotoxicity. Using the BrdU cell proliferation assay, it was found that GA (0.5–2.5 μM) suppressed MDCK and Pkd1 mutant cell proliferation. In addition, GA (0.5–2.5 μM) strongly inhibited phosphorylation of ERK1/2 and S6K expression and upregulated the activation of phosphorylation of AMPK, both in MDCK cells and Pkd1 mutant cells. Taken together, these findings suggested that GA could retard MDCK cyst enlargement, at least in part by inhibiting the cell proliferation pathway. GA could be a natural plant-based drug candidate for ADPKD intervention.

Plant-derived compounds for treating autosomal dominant polycystic kidney disease

“…GA has been shown to inhibit the proliferation of melanoma (95), esophageal squamous carcinoma (99), and glioma cells (100). Khunpatee et al (32) studied the effect of GA on ADPKD in MDCK and PKD1 mutant cells. The results showed that GA inhibits the enlargement of cysts by inhibiting the phosphorylation of the ERK1/2 and mTOR/S6K signaling pathways (32).…”

“…( 32 ) studied the effect of GA on ADPKD in MDCK and PKD1 mutant cells. The results showed that GA inhibits the enlargement of cysts by inhibiting the phosphorylation of the ERK1/2 and mTOR/S6K signaling pathways ( 32 ). In addition, GA can significantly improve the phosphorylation activity of AMPK ( 32 ).…”