Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation.

Abstract

Colorectal cancer is the second most common cause of cancer death in the world and about half of the patients with colorectal cancer require adjuvant therapy after surgical resection. Therefore, the eradication of cancer cells via chemotherapy constitutes a viable approach to treating patients with colorectal cancer. In this study, the effects of bufalin isolated from a traditional Chinese medicine were evaluated and characterized in HT-29 and Caco-2 human colon cancer cells. Contrary to its well-documented apoptosis-promoting activity in other cancer cells, bufalin did not cause caspase-dependent cell death in colon cancer cells, as indicated by the absence of significant early apoptosis as well as poly(ADP-ribose) polymerase and caspase-3 cleavage. Instead, bufalin activated an autophagy pathway, as characterized by the accumulation of LC3-II and the stimulation of autophagic flux. The induction of autophagy by bufalin was linked to the generation of reactive oxygen species (ROS). ROS activated autophagy via the c-Jun NH(2)-terminal kinase (JNK). JNK activation increased expression of ATG5 and Beclin-1. ROS antioxidants (N-acetylcysteine and vitamin C), the JNK-specific inhibitor SP600125, and JNK2 siRNA attenuated bufalin-induced autophagy. Our findings unveil a novel mechanism of drug action by bufalin in colon cancer cells and open up the possibility of treating colorectal cancer through a ROS-dependent autophagy pathway.

• Authors: Chuan-Ming Xie, Wood Yee Chan, Sidney Yu, Jun Zhao, Christopher H K Cheng
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 51 Issue 7 Pg. 1365-75 (Oct 01 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21763418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• ATG5 protein, human
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Bufanolides
• Membrane Proteins
• Microtubule-Associated Proteins
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Reactive Oxygen Species
• Poly(ADP-ribose) Polymerases
• MAP Kinase Kinase 4
• Caspase 3
• bufalin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects)
• Autophagy-Related Protein 5
• Beclin-1
• Blotting, Western
• Bufanolides (pharmacology, therapeutic use)
• Bufonidae
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Gene Expression
• Gene Silencing (drug effects)
• Humans
• MAP Kinase Kinase 4 (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering (pharmacology)
• Reactive Oxygen Species (metabolism)
• Up-Regulation (drug effects, genetics)