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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

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 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

Authors:
;  [1];  [2];  [3];  [4];  [2];  [5];  [6];  [7];  [2]
  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:
22285547
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
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); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; APOPTOSIS; DNA; DRUGS; HYPERGLYCEMIA; INFLAMMATION; LUNGS; MITOCHONDRIA; NEOPLASMS; ORAL ADMINISTRATION; PROTEINS; RIBOSE; TIME DEPENDENCE

Citation Formats

Yoon, Deok Hyo, Lim, Mi-Hee, Lee, Yu Ran, Sung, Gi-Ho, Lee, Tae-Ho, Jeon, Byeong Hwa, Cho, Jae Youl, Song, Won O., Park, Haeil, Choi, Sunga, and Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr. A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.10.015.
Yoon, Deok Hyo, Lim, Mi-Hee, Lee, Yu Ran, Sung, Gi-Ho, Lee, Tae-Ho, Jeon, Byeong Hwa, Cho, Jae Youl, Song, Won O., Park, Haeil, Choi, Sunga, & Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr. A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. United States. https://doi.org/10.1016/J.TAAP.2013.10.015
Yoon, Deok Hyo, Lim, Mi-Hee, Lee, Yu Ran, Sung, Gi-Ho, Lee, Tae-Ho, Jeon, Byeong Hwa, Cho, Jae Youl, Song, Won O., Park, Haeil, Choi, Sunga, and Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr. 2013. "A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells". United States. https://doi.org/10.1016/J.TAAP.2013.10.015.
@article{osti_22285547,
title = {A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells},
author = {Yoon, Deok Hyo and Lim, Mi-Hee and Lee, Yu Ran and Sung, Gi-Ho and Lee, Tae-Ho and Jeon, Byeong Hwa and Cho, Jae Youl and Song, Won O. and Park, Haeil and Choi, Sunga and Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr},
abstractNote = {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 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. - 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.},
doi = {10.1016/J.TAAP.2013.10.015},
url = {https://www.osti.gov/biblio/22285547}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 273,
place = {United States},
year = {Sun Dec 15 00:00:00 EST 2013},
month = {Sun Dec 15 00:00:00 EST 2013}
}