Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 mono-phosphate 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.

Original languageEnglish
Pages (from-to)1893-1903
Number of pages11
JournalMolecular Cancer Therapeutics
Volume20
Issue number10
DOIs
StatePublished - Oct 2021

Bibliographical note

Publisher Copyright:
©2021 American Association for Cancer Research

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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