Physalin A

J Ethnopharmacol. 2013 Jul 9;148(2):544-55.

Physalin A induces apoptosis via p53-Noxa-mediated ROS generation, and autophagy plays a protective role against apoptosis through p38-NF-κB survival pathway in A375-S2 cells.[Pubmed: 23684722]

Physalin A is a bioactive withanolide isolated from natural plant Physalis alkekengi L. var. franchetii (Mast.) Makino, a traditional Chinese herbal medicine named Jindenglong which has long been used for the treatment of cough, sore throat, hepatitis, eczema, dysuria and tumors in China. Based on the previous study that Physalin A induced cytotoxic effect in human melanoma A375-S2 cells, this study was designed to further illustrate the molecular mechanisms underlying.
METHODS AND RESULTS:
Cell viability was evaluated in A375-S2 cells by MTT assay, and the mechanisms involved in Physalin A-induced A375-S2 cell death were investigated by phase contrast microscopy and fluorescence microscopy, siRNA transfection, flow cytometry and western blot analysis. We demonstrated that Physalin A decreased the proportion of viable A375-S2 cells in a time- and dose-dependent manner, and exposure of A375-S2 cells to Physalin A led to both apoptosis and autophagy. Moreover, Physalin A-induced apoptosis was triggered by activation of p53-Noxa pathway and intracellular reactive oxygen species (ROS) generation. The administration of ROS scavengers NAC and GSH resulted in the complete inhibition of Physalin A-induced ROS generation and apoptosis. Application of p53 inhibitor PFT-α or transfection with Noxa-siRNA could also lead to the same results. Autophagy, demonstrated by the punctuate distribution of monodansylcadaverine staining, as well as the change of LC3-II/LC3-I proportion and Beclin 1 activation, played a protective role against apoptosis via up-regulation of the p38-NF-κB survival pathway in A375-S2 cells. Additionally, inhibition of autophagy by the specific autophagic inhibitor 3MA or blocking the p38-NF-κB pathway with p38 inhibitor SB203580 or NF-κB inhibitor PDTC obviously promoted Physalin A-induced apoptosis.
CONCLUSIONS:
Physalin A induced apoptotic cell death via p53-Noxa-mediated ROS generation, and autophagy played a protective role against apoptosis through up-regulating the p38-NF-κB survival pathway in A375-S2 cells. These results stated the possibility that Physalin A would be a potential agent for the treatment of melanoma in the future.

Biol Pharm Bull. 2011;34(10):1584-8.

Physalins A and B inhibit androgen-independent prostate cancer cell growth through activation of cell apoptosis and downregulation of androgen receptor expression.[Pubmed: 21963499]

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).
METHODS AND RESULTS:
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, Physalin A and physalin B down-regulated the expression of prostate specific antigen (PSA) in C42B cells which is a target gene of AR.
CONCLUSIONS:
Our results suggest that Physalin A and physalin B might be useful agents in preventing the growth of androgen-independent prostate cancer (AI-PCa).

Oncotarget. 2016 Feb 23; 7(8): 9462–9476.

Physalin A exerts anti-tumor activity in non-small cell lung cancer cell lines by suppressing JAK/STAT3 signaling[Pubmed: 26843613]

The signal transducers and activators of transcription 3 (STAT3) signaling pathway plays critical roles in the pathogenesis and progression of various human cancers, including non-small cell lung cancer (NSCLC).
METHODS AND RESULTS:
In this study, we aimed to evaluate the therapeutic potential of Physalin A, a bioactive withanolide derived from Physalis alkekengi var. francheti used in traditional Chinese medicine, was evaluated in human NSCLC cells. Its and determined whether it effect oninhibited both constitutive and induced STAT3 activity, through repressing the phosphorylation levels of JAK2 and JAK3, resulting in anti-proliferation and pro-apoptotic effects on NSCLC cells was also determined, and. theThe antitumor effects of Physalin A were also validated usingin an in vivo mouse xenograft models of NSCLC cells. Physalin A had anti-proliferative and pro-apoptotic effects in NSCLC cells with constitutively activated STAT3; it also suppressed both constitutive and induced STAT3 activity by modulating the phosphorylation of JAK2 and JAK3. Furthermore, Physalin A abrogated the nuclear translocation and transcriptional activity of STAT3, thereby decreasing the expression levels of STAT3, its target genes, such as Bcl-2 and XIAP. Knockdown of STAT3 expression by small interfering RNA (siRNA) significantly enhanced the pro-apoptotic effects of Physalin A in NSCLC cells. Moreover, Physalin A significantly suppressed tumor xenograft growth.
CONCLUSIONS:
Thus, as an inhibitor of JAK2/3-STAT3 signaling, Physalin A, has potent anti-tumor activities, which may facilitate the development of a therapeutic strategy for treating NSCLC.

Mol Cell Biochem. 2016 Apr;415(1-2):145-55.

Physalin A induces G2/M phase cell cycle arrest in human non-small cell lung cancer cells: involvement of the p38 MAPK/ROS pathway.[Pubmed: 27000859 ]

Physalin A (PA) is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has long been used for the treatment of sore throat, hepatitis, and tumors in China.
METHODS AND RESULTS:
In the present study, we firstly investigated the effects of PA on proliferation and cell cycle distribution of the human non-small cell lung cancer (NSCLC) A549 cell line, and the potential mechanisms involved. Here, PA inhibited cell growth in dose- and time-dependent manners. Treatment of A549 cells with 28.4 μM PA for 24 h resulted in approximately 50 % cell death. PA increased the amount of intracellular ROS and the proportion of cells in G2/M. G2/M arrest was attenuated by the addition of ROS scavenger NAC. ERK and P38 were triggered by PA through phosphorylation in a time-dependent manner. The phosphorylation of ERK and P38 were not attenuated by the addition of NAC, but the use of the p38 inhibitor could reduce, at least in part, PA-induced ROS and the proportion of cells in G2/M. PA induces G2/M cell cycle arrest in A549 cells involving in the p38 MAPK/ROS pathway.
CONCLUSIONS:
This study suggests that PA might be a promising therapeutic agent against NSCLC.