Novel 2‐step synthetic indole compound 1,1,3‐tri(3‐indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models

BACKGROUND. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.