Cell cycle arrest and apoptosis induced by aspidin PB through the p53/p21 and mitochondria-dependent pathways in human osteosarcoma cells.

Abstract

Aspidin PB is a natural product extracted from Dryopteris fragrans (L.) Schott, which has been characterized for its various biological activities. We reported that aspidin PB induced cell cycle arrest and apoptosis through the p53/p21 and mitochondria-dependent pathways in human osteosarcoma cells. Aspidin PB inhibited the proliferation of Saos-2, U2OS, and HOS cells in a dose-dependent and time-dependent manner. Aspidin PB induced changes in the cell cycle regulators (cyclin A, pRb, CDK2, p53, and p21), which caused cell cycle arrest in the S phase. We also explored the role of siRNA targeted to p53; it led to a dose-dependent attenuation of aspidin PB-induced apoptosis signaling. Moreover, after treatment with aspidin PB, the p21-silenced cells decreased significantly at the S phase. Aspidin PB increased the percentage of cells with mitochondrial membrane potential disruption. Western blot analysis showed that aspidin PB inhibited Bcl-2 expression and induced Bax expression to disintegrate the outer mitochondrial membrane and caused cytochrome C release. Mitochondrial cytochrome C release was associated with the activation of caspase-9 and caspase-3 cascades. Furthermore, the double-stranded DNA breaks and reactive oxygen species signaling were both involved in aspidin PB-induced DNA damage. In addition, aspidin PB inhibited tumor growth significantly in U2OS xenografts. Above all, we conclude that aspidin PB represents a valuable natural source and may potentially be applicable in osteosarcoma therapy.

• Authors: Daqian Wan, Chaoyin Jiang, Xin Hua, Ting Wang, Yimin Chai
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 26 Issue 9 Pg. 931-41 (Oct 2015) ISSN: 1473-5741 [Electronic] England
• PMID: 26181229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclohexanones
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53
• aspidin PB
• Phloroglucinol
• Caspase 3
• Caspase 9

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Bone Neoplasms (drug therapy, pathology)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Cyclohexanones (pharmacology)
• Female
• Heterografts
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• Neoplasm Transplantation
• Osteosarcoma (drug therapy, pathology)
• Phloroglucinol (analogs & derivatives, pharmacology)
• RNA, Small Interfering (genetics)
• S Phase Cell Cycle Checkpoints (drug effects)
• Signal Transduction
• Tumor Suppressor Protein p53 (metabolism)