Supercritical Fluid Extraction of Citrus iyo Hort. ex Tanaka Pericarp Inhibits Growth and Induces Apoptosis Through Abrogation of STAT3 Regulated Gene Products in Human Prostate Cancer Xenograft Mouse Model.

Abstract

Activation of signal transducer and activator of transcription 3 (STAT3) is well known to play a major role in the cell growth, survival, proliferation, metastasis, and angiogenesis of various cancer cells. Most of the citrus species offer large quantities of phytochemicals that have beneficial effects attributed to their chemical components. Our study was carried out to evaluate the anticancer effects of the pericarp of Iyokan ( Citrus iyo Hort. ex Tanaka), locally known as yeagam in Korea, through modulation of the STAT3 signaling pathway in both tumor cells and a nude mice model. The effect of supercritical extracts of yeagam peel (SEYG) on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of SEYG on the growth of DU145 human prostate xenograft tumors in athymic nu/nu male mice was also investigated. We found SEYG exerted substantial inhibitory effect on STAT3 activation in human prostate cancer DU145 cells as compared to other tumor cells analyzed. SEYG inhibited proliferation and downregulated the expression of various STAT3-regulated gene products such as bcl-2, bcl-xL, survivin, IAP-1/2, cyclin D1, cyclin E, COX-2, VEGF, and MMP-9. This correlated with an increase in apoptosis as indicated by an increase in the expression of p53 and p21 proteins, the sub-G1 arrest, and caspase-3-induced PARP cleavage. When administered intraperitoneally, SEYG reduced the growth of DU145 human prostate xenograft tumors through downmodulation of STAT3 activation in athymic nu/nu male mice. Overall, these results suggest that SEYG extract has the potential source of STAT3 inhibitors that may have a potential in chemoprevention of human prostate cancer cells.

• Authors: Chulwon Kim, Il Ho Lee, Ho Bong Hyun, Jong-Chan Kim, Rajendra Gyawali, Seok-Geun Lee, Junhee Lee, Sung-Hoon Kim, Bum Sang Shim, Somi K Cho, Kwang Seok Ahn
• Journal: Integrative cancer therapies (Integr Cancer Ther) Vol. 16 Issue 2 Pg. 227-243 (06 2017) ISSN: 1552-695X [Electronic] United States
• PMID: 27185319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Citrus (chemistry)
• Humans
• K562 Cells
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (drug therapy, metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Signal Transduction (drug effects)