Physalins A and B Inhibit Androgen-Independent Prostate Cancer Cell Growth through Activation of Cell Apoptosis and Downregulation of Androgen Receptor Expression
Biological and Pharmaceutical Bulletin
Prostate cancer is the second leading cause of cancer-related deaths in American males. 1) When diagnosed with advanced prostate cancer, androgen depletion therapy would initially be used to treat these patients. 2) The majority of patients would respond to the treatment and resulting in shrinkage of tumors. Unfortunately, relapse of tumors often occur in most of the patients, leading to androgen-independent prostate cancers (AI-PCa). Currently, there is no curative therapy for AI-PCa. 3) The
... act molecular mechanisms responsible for the development of AI-PCa are not understood. The available data support the significance of the expression and activity of androgen receptor (AR) in AI-PCa progression. In a relatively large number of AI-PCa patients, AR is expressed, overexpressed, mutated or amplified. 4,5) AR itself may exert an important function in PCa progression and has been a promising target for treating AI-PCa. Natural products have become more and more attractive in the treatment of cancers, therefore, we focused on natural products as a source for screening active components that target AR signaling pathway and inhibit cell growth in PCa cell lines. Our previous study showed that lignans from Campylotropishirtella (FRANCH.) SCHINDL. significantly down-regulated AR expression and also its target gene, prostate specific antigen (PSA), in an androgen dependent cell line, LNCaP, for the first time. 6) The compound that showed the best activity on AR inhibition also significantly inhibited cell growth. In this study, we further investigated two natural compounds, physalins A and B, both secosteriods isolated from Physalisalkekengi var. franchetii and provided by Qiu. 7) In China, the calyces of Physalisalkekengi var. franchetii (Solanaceae) have been used as a herb for the treatment of many diseases including tumors. 8) Physalins are the major steroidal constituents of P. alkekengi var. franchetii. In particular, physalins A and B are found in high concentrations in P. alkekengi var. franchetii. Previous reports have Androgen deprivation therapy is a common treatment strategy for advanced prostate cancer. Though effective initially, the tumor often progresses to androgen independent stage in most patients eventually after a period of remission. One of the key factors of development of resistance is reflected in expression of androgen receptor (AR). In this study, we showed that two natural compounds, physalins A and B, both secosteriods from Physalisalkekengi var. franchetii, significantly inhibited the growth of two androgen-independent cell lines CWR22Rv1 and C42B, induced apoptosis via c-Jun N-terminal kinase (JNK) and/or extracellular signal-regulated kinase (ERK) activation, and decreased AR expression. In addition, physalins A and B down-regulated the expression of prostate specific antigen (PSA) in C42B cells which is a target gene of AR. Our results suggest that physalin A and B might be useful agents in preventing the growth of androgen-independent prostate cancer (AI-PCa).