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

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 IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G{sub 0}/G{sub 1}-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 exhibitedmore » 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. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by the ROS generation through MAPKs. • The MA-1-induced cell death was also modulated by the mitochondria-mediated pathway. • The apoptotic cancer cell death by MA-1 was also exhibited in orthotopic xenografts. • Our findings suggest MA-1 as a clinically useful agent for human lung cancer.« less
;  [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [5] ;  [6] ;  [7] ;  [2] ;  [1]
  1. Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)
  2. Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of)
  3. Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Suwon 404-707 (Korea, Republic of)
  4. R and D Center, Dong-A Pharmaceutical Co, Ltd, Yongin 446-905 (Korea, Republic of)
  5. Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of)
  6. Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824 (United States)
  7. College of Pharmacy, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)
Publication Date:
OSTI Identifier:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 273; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States