Potent Synergistic Effect on C-Myc-Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor.
Yanqi XieWen ZhangLichao GuoLiliia M KrilKristin L BegleyVitaliy M SviripaXi ChenXifu LiuEun Y LeeDaheng HeChi WangTianyan GaoXiaoqi LiuB Mark EversDavid S WattChunming LiuPublished in: Molecular cancer therapeutics (2021)
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.
Keyphrases
- small molecule
- molecular docking
- protein kinase
- transcription factor
- emergency department
- protein protein
- systemic lupus erythematosus
- young adults
- cell therapy
- high throughput
- papillary thyroid
- climate change
- drug induced
- disease activity
- combination therapy
- mesenchymal stem cells
- electronic health record
- human health
- lymph node metastasis