Reevesioside A, a cardenolide glycoside, induces anticancer activity against human hormone-refractory prostate cancers through suppression of c-myc expression and induction of G1 arrest of the cell cycle.

Abstract

In the past decade, there has been a profound increase in the number of studies revealing that cardenolide glycosides display inhibitory activity on the growth of human cancer cells. The use of potential cardenolide glycosides may be a worthwhile approach in anticancer research. Reevesioside A, a cardenolide glycoside isolated from the root of Reevesia formosana, displayed potent anti-proliferative activity against human hormone-refractory prostate cancers. A good correlation (r² = 0.98) between the expression of Na⁺/K⁺-ATPase α₃ subunit and anti-proliferative activity suggested the critical role of the α₃ subunit. Reevesioside A induced G1 arrest of the cell cycle and subsequent apoptosis in a thymidine block-mediated synchronization model. The data were supported by the down-regulation of several related cell cycle regulators, including cyclin D1, cyclin E and CDC25A. Reevesioside A also caused a profound decrease of RB phosphorylation, leading to an increased association between RB and E2F1 and the subsequent suppression of E2F1 activity. The protein and mRNA levels of c-myc, which can activate expression of many downstream cell cycle regulators, were dramatically inhibited by reevesioside A. Transient transfection of c-myc inhibited the down-regulation of both cyclin D1 and cyclin E protein expression to reevesioside A action, suggesting that c-myc functioned as an upstream regulator. Flow cytometric analysis of JC-1 staining demonstrated that reevesioside A also induced the significant loss of mitochondrial membrane potential. In summary, the data suggest that reevesioside A inhibits c-myc expression and down-regulates the expression of CDC25A, cyclin D1 and cyclin E, leading to a profound decrease of RB phosphorylation. G1 arrest is, therefore, induced through E2F1 suppression. Consequently, reevesioside A causes mitochondrial damage and an ultimate apoptosis in human hormone-refractory prostate cancer cells.

• Authors: Wohn-Jenn Leu, Hsun-Shuo Chang, She-Hung Chan, Jui-Ling Hsu, Chia-Chun Yu, Lih-Ching Hsu, Ih-Sheng Chen, Jih-Hwa Guh
• Journal: PloS one (PLoS One) Vol. 9 Issue 1 Pg. e87323 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24475272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cardenolides
• DNA Primers
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• reevesioside A
• Calcium

Topics

• Analysis of Variance
• Antineoplastic Agents (pharmacology, therapeutic use)
• Blotting, Western
• Calcium (metabolism)
• Cardenolides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Primers (genetics)
• Flow Cytometry
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Male
• Membrane Potential, Mitochondrial
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Proto-Oncogene Proteins c-myc (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction