Cytotoxic withanolides from Physalis angulata var. villosa and the apoptosis-inducing effect via ROS generation and the activation of MAPK in human osteosarcoma cells

Withanolides are a large group of steroidal lactones found in Solanaceae plants that exhibit potential anticancer activities. In the present study, eight new withanolides, physagulides A-H (1-8), along with ten known analogues (9-18), were isolated and identified from the whole plants of Physalis angulata var. villosa. All compounds were evaluated for their cytotoxicity against three human cancer cell lines, human hepatoma (HepG2), human breast carcinoma (MCF-7) and human osteosarcoma (MG-63) cells. Compounds 9, 10, 14, 17 and 18 exhibited cytotoxicity on all cell lines with half maximal inhibitory concentration (IC50) values of 0.06-6.73 mu M, comparable to those of the reference agent cisplatin. One of the potent compounds, physagulide I (9) arrested cells in the G(2)/M phase and activated caspase-dependent apoptotic pathways. Furthermore, apoptosis induced by physagulide I in MG-63 cells was associated with the generation of reactive oxygen species (ROS) and the activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK). These results suggest that physagulide I may be a promising agent for the treatment of cancer.