New withanolides with TRAIL-sensitizing effect fromPhysalis pubescensL.
Physalis pubescensL. 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 ofP. pubescensL. and their chemical structures were established by extensive spectroscopic analyses. Compounds1,3and5showed 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, compound1was the most potent one with IC50s ranged from 0.30 to 0.77μM. Further experiment showed that1sensitized 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 compound1could 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 inP. pubescensL. and deserves further investigation for RCC prevention and treatment.
Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Department of Urology, University of California, Irvine, Orange, CA 92868, USA.
Li-Xia
LX
Chen
Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People's Republic of China.
Gui-Yang
GY
Xia
School of Pharmaceutical Sciences, Xi' an Medical University, Xi' an 710021, People's Republic of China.
Hao
H
He
Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Jian
J
Huang
Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People's Republic of China.
Feng
F
Qiu
Department of Urology, University of California, Irvine, Orange, CA 92868, USA.
Xiao-Lin
XL
Zi