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.

• Authors: Yanqi Xie, Wen Zhang, Lichao Guo, Liliia M Kril, Kristin L Begley, Vitaliy M Sviripa, Xi Chen, Xifu Liu, Eun Y Lee, Daheng He, Chi Wang, Tianyan Gao, Xiaoqi Liu, B Mark Evers, David S Watt, Chunming Liu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 10 Pg. 1893-1903 (10 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34376582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• 5-(7-chloroquinolin-4-ylamino)-2-diethylaminomethylphenol
• BI 2536
• Cell Cycle Proteins
• MYC protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-myc
• Pteridines
• Amodiaquine
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Amodiaquine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Proliferation
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Drug Synergism
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pteridines (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays