We have purified physapubescin, a predominant steroidal lactone, from medicinal plant Physalis pubescens L., commonly named as "hairy groundcherry" in English and "Deng-Long-Cao" in Chinese. Von Hippel-Lindau (VHL)-null 786-O, RCC4 and A498 Renal Cell Carcinoma (RCC) cell lines expressing high levels of Hypoxia Inducible Factor (HIF)-2α are more sensitive to physapubescin-mediated apoptosis and growth inhibitory effect than VHL wild-type Caki-2 and ACHN RCC cell lines. Restoration of VHL in RCC4 cells attenuated the growth inhibitory effect of physapubescin. Physapubescin decreases the expression of HIF-2α and increases the expression of CCAAT/enhancer-binding protein homologus protein (CHOP), which leads to up-regulation of death receptor 5 (DR5), activation of caspase-8 and -3, cleavage of poly (ADP-Ribose) polymerase (PARP) and apoptosis. Under hypoxia conditions, the apoptotic and growth inhibitory effects of physapubescin are further enhanced. Additionally, physapubescin synergizes with TNF-related apoptosis-inducing ligand (TRAIL) for markedly enhanced induction of apoptosis in VHL-null 786-O cells but not in VHL wild-type Caki-2 cells. Physapubescin significantly inhibited in vivo angiogenesis in the 786-O xenograft. Physapubescin as a novel agent for elimination of VHL-null RCC cells via apoptosis is warranted for further investigation.
Scientific reports. 2016 Sep 01*** epublish ***
Lixia Chen, Guiyang Xia, Feng Qiu, Chunli Wu, Andria P Denmon, Xiaolin Zi
Departments of Urology and Pharmacology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA., 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, P. R. China., School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P. R. China.