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Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models†
Article first published online: 10 JUL 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 4, pages 815–825, 15 August 2008
How to Cite
Lee, C.-H., Yao, C.-F., Huang, S.-M., Ko, S., Tan, Y.-H., Lee-Chen, G.-J. and Wang, Y.-C. (2008), Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models. Cancer, 113: 815–825. doi: 10.1002/cncr.23619
Request for description of the preparation and chemical information for 1,1,3-tri(3-indolyl)cyclohexane (3-indole): Ching-Fa Yao, PhD, Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan, ROC. Fax: (011) 886-2-29324249; E-mail: firstname.lastname@example.org
- Issue published online: 1 AUG 2008
- Article first published online: 10 JUL 2008
- Manuscript Accepted: 4 APR 2008
- Manuscript Revised: 21 MAR 2008
- Manuscript Received: 29 JAN 2008
- National Science Council (Executive Yuan, Republic of China). Grant Numbers: DOH96-TD-G-111-004, NSC96-2628-B-006-048-MY3, NSC96-2627-M-006-005
- indole compound;
- lung cancer;
- mitochondria-mediated apoptosis;
- reactive oxygen species;
- c-Jun N-terminal kinase
The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed.
A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed.
The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3-Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models.
On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment. Cancer 2008. © 2008 American Cancer Society.