1. Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor
- Author
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Daheng He, Lichao Guo, David S. Watt, Eun Y. Lee, Kristin L. Begley, Xiaoqi Liu, Wen Zhang, Tianyan Gao, B. Mark Evers, Vitaliy M. Sviripa, Liliia M. Kril, Yanqi Xie, Xifu Liu, Chi Wang, Xi Chen, and Chunming Liu
- Subjects
Male ,Adenosine monophosphate ,Cancer Research ,Colorectal cancer ,Mice, Nude ,Apoptosis ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,PLK1 ,Article ,Proto-Oncogene Proteins c-myc ,Mice ,chemistry.chemical_compound ,In vivo ,Proto-Oncogene Proteins ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Cell Proliferation ,Kinase ,Pteridines ,Wnt signaling pathway ,Amodiaquine ,AMPK ,Drug Synergism ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Oncology ,chemistry ,Cancer research ,Female ,Colorectal Neoplasms - Abstract
Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as N7,N7-dimethyl-3-(1-methyl-1H-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent in vitro inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy–homeostasis master regulator. We explored the effect of ISQs on cell metabolism. Seahorse assays measuring oxygen consumption rate (OCR) indicated that ISQ-1 inhibited complex I (i.e., NADH ubiquinone oxidoreductase) in the mitochondrial, electron transport chain (ETC). In addition, ISQ-1 treatment showed remarkable synergistic depletion of oncogenic c-Myc protein level in vitro and induced strong tumor remission in vivo when administered together with BI2536, a polo-like kinase-1 (Plk1) inhibitor. These studies point toward the potential value of dual drug therapies targeting the ETC and Plk-1 for the treatment of c-Myc–driven cancers.
- Published
- 2021