Paris saponin VII induces cell cycle arrest and apoptosis by regulating Akt/MAPK pathway and inhibition of P‐glycoprotein in K562/ADR cells

• Published in: Phytotherapy research Vol. 32; no. 5; pp. 898 - 907
• Main Authors: Yan, Ting, Hu, Gaosheng, Wang, Anhua, Sun, Xianduo, Yu, Xiangyong, Jia, Jingming
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.05.2018
• Subjects: AKT protein; Akt/MAPK pathway; Apoptosis; Autophagy; Bax protein; Caspase; Cell cycle; cell cycle arrest; Cell proliferation; Cyclin B1; Cyclin-dependent kinase 2; Cytochrome; Cytochrome c; Cytotoxicity; G1 phase; Glycoproteins; Inhibition; JNK protein; Leukemia; MAP kinase; Membrane potential; Mitochondria; Molecular chains; Paris saponin VII; Phagocytosis; Poly(ADP-ribose) polymerase; Protein expression; Proteins; P‐glycoprotein; Reactive oxygen species; Rhizomes; Therapeutic applications; Toxicity; P-glycoprotein; apoptosis; Akt/MAPK pathway; Paris saponin VII; cell cycle arrest
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.6029

Paris saponinVII (PSVII) is a steroidal saponin isolated from the roots and rhizomes of Trillium tschonoskii Maxim. We found that PSVII could inhibit the growth of adriamycin‐resistant human leukemia cells (K562/ADR) in a dose‐dependent manner. Furthermore, the molecular mechanism underlying the cytotoxicity and downregulation of P‐glycoprotein (P‐gp) expression by PSVII was clarified. PSVII significantly suppressed cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious decrease in cyclin B1/D1 and CDK2/4/6 protein expression. Moreover, PSVII could attenuate mitochondrial membrane potential, increase the expression of apoptosis‐related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl‐2, caspase‐9, caspase‐3, PARP‐1, and p‐Akt. We also found that JNK, ERK1/2, and p38 were regulated by PSVII in K562/ADR cells. And further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P‐gp expression. Therefore, PSVII‐induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P‐gp. In addition, PSVII induced a robust autophagy in K562/ADR cells as demonstrated by the degradation of LC3‐I. These results provide a biochemical basis for possible clinical applications of PSVII in the treatment of leukemia.