A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells.

Abstract

A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC50 of 5μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G0/G1-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer.

• Authors: Deok Hyo Yoon, Mi-Hee Lim, Yu Ran Lee, Gi-Ho Sung, Tae-Ho Lee, Byeong Hwa Jeon, Jae Youl Cho, Won O Song, Haeil Park, Sunga Choi, Tae Woong Kim
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 273 Issue 3 Pg. 659-71 (Dec 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 24161344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Antineoplastic Agents
• BAX protein, human
• Glucosides
• Malates
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• bis(4-(glucopyranosyloxy)benzyl) 2-sec-butylmalate
• Cytochromes c
• Poly(ADP-ribose) Polymerases
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cytochromes c (metabolism)
• DNA Fragmentation (drug effects)
• Female
• Glucosides (chemical synthesis, pharmacology)
• Humans
• Inhibitory Concentration 50
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• Lung Neoplasms (metabolism)
• Malates (chemical synthesis, pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• bcl-2-Associated X Protein (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)