Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 Inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells

Lichao Guo, Wen Zhang, Yanqi Xie, Xi Chen, Emma E. Olmstead, Mengqiang Lian, Baochen Zhang, Yekaterina Y. Zaytseva, B. Mark Evers, H. Peter Spielmann, Xifu Liu, David S. Watt, Chunming Liu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Cancer cells undergo significant “metabolic remodeling” to provide sufficient ATP to maintain cell survival and to promote rapid growth. In colorectal cancer cells, ATP is produced by mitochondrial oxidative phosphorylation and by substantially elevated cytoplasmic glucose fermentation (i.e., the Warburg effect). Glucose transporter 1 (GLUT1) expression is significantly increased in colorectal cancer cells, and GLUT1 inhibitors block glucose uptake and hence glycolysis crucial for cancer cell growth. In addition to ATP, these metabolic pathways also provide macro-molecule building blocks and signaling molecules required for tumor growth. In this study, we identify a diaminobutoxy-substituted isoflavonoid (DBI-1) that inhibits mitochondrial complex I and deprives rapidly growing cancer cells of energy needed for growth. DBI-1 and the GLUT1 inhibitor, BAY-876, synergistically inhibit colorectal cancer cell growth in vitro and in vivo. This study suggests that an electron transport chain inhibitor (i.e., DBI-1) and a glucose transport inhibitor, (i.e., BAY-876) are potentially effective combination for colorectal cancer treatment.

Original languageEnglish
Pages (from-to)740-750
Number of pages11
JournalMolecular Cancer Therapeutics
Volume21
Issue number5
DOIs
StatePublished - May 2022

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. X. Liu reports a patent for 63/286,303, pending. 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 63/286,303 pending. No disclosures were reported by the other authors.

Funding Information:
C. Liu and D.S. Watt were supported by NIH R01 CA172379 from the NIH 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 and NIH P30 RR020171 from the National Institute of General Medical Sciences to L. Hersh. 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).

Publisher Copyright:
© 2022 American Association for Cancer Research

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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