Swainsonine activates mitochondria-mediated apoptotic pathway in human lung cancer A549 cells and retards the growth of lung cancer xenografts.

Abstract

Swainsonine (1, 2, 8-trihyroxyindolizidine, SW), a natural alkaloid, has been reported to exhibit anti-cancer activity on several mouse models of human cancer and human cancers in vivo. However, the mechanisms of SW-mediated tumor regression are not clear. In this study, we investigated the effects of SW on several human lung cancer cell lines in vitro. The results showed that SW significantly inhibited these cells growth through induction of apoptosis in different extent in vitro. Further studies showed that SW treatment up-regulated Bax, down-regulated Bcl-2 expression, promoted Bax translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, which in turn caused the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), resulting in A549 cell apoptosis. However, the expression of Fas, Fas ligand (FasL) or caspase-8 activity did not appear significant changes in the process of SW-induced apoptosis. Moreover, SW treatment inhibited Bcl-2 expression, promoted Bax translocation, cytochrome c release and caspase-3 activity in xenograft tumor cells, resulting in a significant decrease of tumor volume and tumor weight in the SW-treated xenograft mice groups in comparison to the control group. Taken together, this study demonstrated for the first time that SW inhibited A549 cancer cells growth through a mitochondria-mediated, caspase-dependent apoptotic pathway in vitro and in vivo.

• Authors: Zhaocai Li, Xingang Xu, Yong Huang, Li Ding, Zhisheng Wang, Gaoshui Yu, Dan Xu, Wei Li, Dewen Tong
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 8 Issue 3 Pg. 394-405 ( 2012) ISSN: 1449-2288 [Electronic] Australia
• PMID: 22393311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Apoptosis Regulatory Proteins
• Neoplasm Proteins
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• Swainsonine

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (biosynthesis, genetics)
• Caspase 3 (physiology)
• Caspase 9 (physiology)
• Cell Line, Tumor (drug effects, transplantation)
• Enzyme Activation
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (drug effects)
• Neoplasm Proteins (biosynthesis, genetics)
• Swainsonine (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays