New withanolides with TRAIL-sensitizing effect from Physalis pubescens L.

Physalis pubescens L. plant produces nutritious and healthy fruits, called husk tomato or hairy ground cherry. However, its bioactive components are largely unknown. Four new withanolide steroids (1-4) together with one known withanolide (5) were isolated from the extract of P. pubescens L. and their chemical structures were established by extensive spectroscopic analyses. Compounds 1, 3 and 5 showed potent growth inhibitory effects against four human renal cell carcinoma (RCC) cell lines (i.e. 786-O, A-498, Caki-2 and ACHN). Among them, compound 1 was the most potent one with IC50s ranged from 0.30 to 0.77 μM. Further experiment showed that 1 sensitized human RCC cells 786-O to the tumor necrosis factor related apoptosis ligand (TRAIL)-induced apoptosis and increased the expression of C/EBP-homologous protein (CHOP) and death receptor-5 (DR5), leading to activation of the DR5 and caspase-8/3 mediated apoptosis pathway. Molecular docking analysis revealed that compound 1 could bind stably to the TRAIL/DR5 complex through hydrogen bonds. These results suggest that the new withanolide (1) is a lead anti-cancer compound existing in P. pubescens L. and deserves further investigation for RCC prevention and treatment.