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

doi:10.1158/1535-7163.MCT-20-1017

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 journal › Article › peer-review

3 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 language	English
Pages (from-to)	1893-1903
Number of pages	11
Journal	Molecular Cancer Therapeutics
Volume	20
Issue number	10
DOIs	https://doi.org/10.1158/1535-7163.MCT-20-1017
State	Published - Oct 2021

Bibliographical note

Funding Information:
W. Zhang reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work. C. Liu reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work; in addition, C. Liu has a patent for application No. 63/213,584 pending. No disclosures were reported by the other authors.

Funding Information:
Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558).

Funding Information:
C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky?s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558).

Funding Information:
C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky’s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National

Publisher Copyright:
©2021 American Association for Cancer Research

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1535-7163.MCT-20-1017

Cite this

Xie, Y., Zhang, W., Guo, L., Kril, L. M., Begley, K. L., Sviripa, V. M., Chen, X., Liu, X., Lee, E. Y., He, D., Wang, C., Gao, T., Liu, X., Evers, B. M., Watt, D. S., & Liu, C. (2021). Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor. Molecular Cancer Therapeutics, 20(10), 1893-1903. https://doi.org/10.1158/1535-7163.MCT-20-1017

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title = "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 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.",

author = "Yanqi Xie and Wen Zhang and Lichao Guo and Kril, {Liliia M.} and Begley, {Kristin L.} and Sviripa, {Vitaliy M.} and Xi Chen and Xifu Liu and Lee, {Eun Y.} and Daheng He and Chi Wang and Tianyan Gao and Xiaoqi Liu and Evers, {B. Mark} and Watt, {David S.} and Chunming Liu",

note = "Funding Information: W. Zhang reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work. C. Liu reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work; in addition, C. Liu has a patent for application No. 63/213,584 pending. No disclosures were reported by the other authors. Funding Information: Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558). Funding Information: C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky?s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558). Funding Information: C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky{\textquoteright}s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National Publisher Copyright: {\textcopyright}2021 American Association for Cancer Research",

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doi = "10.1158/1535-7163.MCT-20-1017",

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Xie, Y, Zhang, W, Guo, L, Kril, LM, Begley, KL, Sviripa, VM, Chen, X, Liu, X, Lee, EY, He, D, Wang, C , Gao, T , Liu, X , Evers, BM, Watt, DS & Liu, C 2021, 'Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor', Molecular Cancer Therapeutics, vol. 20, no. 10, pp. 1893-1903. https://doi.org/10.1158/1535-7163.MCT-20-1017

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T1 - Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor

AU - Xie, Yanqi

AU - Zhang, Wen

AU - Guo, Lichao

AU - Kril, Liliia M.

AU - Begley, Kristin L.

AU - Sviripa, Vitaliy M.

AU - Chen, Xi

AU - Liu, Xifu

AU - Lee, Eun Y.

AU - He, Daheng

AU - Wang, Chi

AU - Gao, Tianyan

AU - Liu, Xiaoqi

AU - Evers, B. Mark

AU - Watt, David S.

AU - Liu, Chunming

N1 - Funding Information: W. Zhang reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work. C. Liu reports grants from NIH during the conduct of the study; other support from Epionc Inc. outside the submitted work; in addition, C. Liu has a patent for application No. 63/213,584 pending. No disclosures were reported by the other authors. Funding Information: Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558). Funding Information: C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky?s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). V.M. Sviripa was supported by grant IRG 16-182-28 from the American Cancer Society). This research was supported by Biostatistics & Bioinformatics Shared Resource Facility (BB SRF), the Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) and the Redox Metabolism Shared Resource Facility (RM SRF) of the University of Kentucky Markey Cancer Center (P30CA177558). Funding Information: C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH and by NIH UL1 TR000117 from the NIH to the University of Kentucky’s Center for Clinical and Translational Science and by Markey Cancer Center Alliance Award. D.S. Watt was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense [DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 (grant Log# PC150326P2)], and NIH P30 RR020171 from the National Publisher Copyright: ©2021 American Association for Cancer Research

PY - 2021/10

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N2 - 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.

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

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