Smac peptide potentiates TRAIL- or paclitaxel-mediated ovarian cancer cell death in vitro and in vivo.

Abstract

Second mitochondria-derived activator of caspases (Smac) is a recently identified protein that is released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing the inhibitor of apoptosis proteins (IAPs). Our previous study showed that ectopic overexpression of Smac sensitizes drug-resistant tumor cells to TRAIL- or paclitaxel-induced apoptosis in vitro. The present study was designed to explore the effect of the synthesized Smac N7 peptide in a human ovarian cancer cell line and xenograft model. The results showed that the single-agent Smac N7 had a non-cytotoxic effect, but it effectively enhanced TRAIL- or paclitaxel-induced inhibition of cell proliferation in a dose-dependent manner, even in TRAIL-resistant A2780 cells. When Smac N7 was combined with TRAIL or paclitaxel in treating A2780 cell tumor xenografts, synergistic anticancer effects were achieved. Furthermore, the combination therapy caused less damage in normal tissues and more apoptosis in tumor xenografts compared with TRAIL or paclitaxel alone. Increased apoptosis was associated with the downregulation of XIAP, survivin and the increased activity of caspase-3, along with an increased amount of cleaved PARP. In conclusion, this Smac N7 peptide is a promising candidate for ovarian cancer combination therapy, and Smac may be the target for the development of a novel class of anticancer drugs.

• Authors: Hong Luan Mao, Yingxin Pang, Xiaolei Zhang, Fang Yang, Jingfang Zheng, Yu Wang, Peishu Liu
• Journal: Oncology reports (Oncol Rep) Vol. 29 Issue 2 Pg. 515-22 (Feb 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23151974 (Publication Type: Journal Article)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Oligopeptides
• Proto-Oncogene Proteins c-bcl-2
• SMAC peptide
• Survivin
• TNF-Related Apoptosis-Inducing Ligand
• X-Linked Inhibitor of Apoptosis Protein
• Caspase 3
• Paclitaxel

Topics

• Analysis of Variance
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Ovarian Epithelial
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Down-Regulation (drug effects)
• Drug Synergism
• Female
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Necrosis (chemically induced)
• Neoplasms, Glandular and Epithelial (drug therapy, metabolism)
• Oligopeptides (pharmacokinetics, pharmacology)
• Ovarian Neoplasms (drug therapy, metabolism)
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Skin (pathology)
• Survivin
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)