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A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells.
Toxicol Appl Pharmacol. 2013 Dec 15; 273(3):659-71.TA

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+Show Affiliations

Department of Biochemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24161344

Citation

Yoon, Deok Hyo, et al. "A Novel Synthetic Analog of Militarin, MA-1 Induces Mitochondrial Dependent Apoptosis By ROS Generation in Human Lung Cancer Cells." Toxicology and Applied Pharmacology, vol. 273, no. 3, 2013, pp. 659-71.
Yoon DH, Lim MH, Lee YR, et al. A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. Toxicol Appl Pharmacol. 2013;273(3):659-71.
Yoon, D. H., Lim, M. H., Lee, Y. R., Sung, G. H., Lee, T. H., Jeon, B. H., Cho, J. Y., Song, W. O., Park, H., Choi, S., & Kim, T. W. (2013). A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. Toxicology and Applied Pharmacology, 273(3), 659-71. https://doi.org/10.1016/j.taap.2013.10.015
Yoon DH, et al. A Novel Synthetic Analog of Militarin, MA-1 Induces Mitochondrial Dependent Apoptosis By ROS Generation in Human Lung Cancer Cells. Toxicol Appl Pharmacol. 2013 Dec 15;273(3):659-71. PubMed PMID: 24161344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. AU - Yoon,Deok Hyo, AU - Lim,Mi-Hee, AU - Lee,Yu Ran, AU - Sung,Gi-Ho, AU - Lee,Tae-Ho, AU - Jeon,Byeong Hwa, AU - Cho,Jae Youl, AU - Song,Won O, AU - Park,Haeil, AU - Choi,Sunga, AU - Kim,Tae Woong, Y1 - 2013/10/22/ PY - 2013/07/27/received PY - 2013/10/04/revised PY - 2013/10/14/accepted PY - 2013/10/29/entrez PY - 2013/10/29/pubmed PY - 2014/2/11/medline KW - Human lung cancer cells KW - JNK/p38 MAPK KW - Militarin analog-1 (MA-1) KW - Mitochondria mediated apoptosis KW - Orthotopic xenograft KW - Reactive oxygen species SP - 659 EP - 71 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 273 IS - 3 N2 - 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/24161344/A_novel_synthetic_analog_of_Militarin_MA_1_induces_mitochondrial_dependent_apoptosis_by_ROS_generation_in_human_lung_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(13)00463-8 DB - PRIME DP - Unbound Medicine ER -