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Toxicol Appl Pharmacol. 2013 Dec 15;273(3):659-71. doi: 10.1016/j.taap.2013.10.015. Epub 2013 Oct 22.

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

Author information

1
Department of Biochemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea.

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.

KEYWORDS:

Human lung cancer cells; JNK/p38 MAPK; Militarin analog-1 (MA-1); Mitochondria mediated apoptosis; Orthotopic xenograft; Reactive oxygen species

PMID:
24161344
DOI:
10.1016/j.taap.2013.10.015
[Indexed for MEDLINE]

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