Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 10, 2021
- Source ID
- 10.1158/1535-7163.mct-20-1017
Entities
People
- B Mark Evers
- Chi Wang
- Chunming Liu
- Daheng He
- David S Watt
- Eun Y. Lee
- Kristin L. Begley
- Lichao Guo
- Liliia M. Kril
- Tianyan Gao
- Vitaliy M Sviripa
- Wen Zhang
- Xi Chen
- Xiaoqi Liu
- Xifu Liu
- Yanqi Xie
Organizations
- American Cancer Society
- Hebei Normal University
- National Institute of General Medical Sciences
- National Institutes of Health
- United States Department of Defense
- University of Kentucky