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Discovery of New Glucose Uptake Inhibitors as Potential Anticancer Agents by Non-Radioactive Cell-Based Assays
Hsueh-Chih Hung1, Li-Cheng Li1, Jih-Hwa Guh1
1School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10617, Taiwan.
Abstract:
Tumor cells rely on aerobic glycolysis to support growth and survival, thus require more glucose supply. Glucose transporters GLUTs, primarily GLUT1, are overexpressed in various cancers. Targeting GLUTs has been regarded as a promising anticancer strategy. In this study, we first evaluated 75 potential GLUT1 inhibitors obtained from virtual screening of the NCI chemical library by a high-throughput cell-based method using a fluorescent glucose analogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-d-glucose (2-NBDG) in COS-7 and SKOV3 cells that express high levels of GLUT1. Four compounds, #12, #16, #43 and #69, that significantly inhibited glucose uptake were further evaluated using flow cytometry directly measuring 2-NBDG uptake at the single-cell level and a Glucose Uptake-GloTM assay indirectly measuring 2-deoxy-d-glucose uptake in SKOV3, COS-7 or MCF-7 cells. The inhibitory effect on cancer cell growth was also determined in SKOV3 and MCF-7 cells, and #12 exhibited the best growth inhibitory effect equivalent to a known GLUT1 inhibitor WZB117. Although the anticancer effect of the identified potential GLUT1 inhibitors was moderate, they may enhance the activity of other anticancer drugs. Indeed, we found that #12 synergistically enhanced the anticancer activity of metformin in SKOV3 ovarian cancer cells.
Insights
Researchers screened 75 compounds to find GLUT1 inhibitors for cancer therapy. Compound #12 showed significant cancer cell growth inhibition and synergistic effects with metformin, offering a promising strategy for ovarian cancer treatment.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Tumor cells exhibit increased aerobic glycolysis, necessitating enhanced glucose uptake.
- Glucose transporter 1 (GLUT1) is overexpressed in many cancers, making it a potential therapeutic target.
- Targeting GLUT1 offers a promising strategy for developing novel anticancer therapies.
Purpose of the Study:
- To identify novel GLUT1 inhibitors from the NCI chemical library.
- To evaluate the efficacy of identified inhibitors in reducing glucose uptake and inhibiting cancer cell growth.
- To assess the potential synergistic effect of identified inhibitors with existing anticancer drugs.
Main Methods:
- High-throughput screening of 75 NCI compounds using 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-d-glucose (2-NBDG) in COS-7 and SKOV3 cells.
- Flow cytometry and Glucose Uptake-Glo assay to measure glucose uptake in cancer cells (SKOV3, COS-7, MCF-7).
- Assessment of cancer cell growth inhibition and drug synergy studies.
Main Results:
- Four compounds (#12, #16, #43, #69) significantly inhibited glucose uptake.
- Compound #12 demonstrated the strongest growth inhibitory effect, comparable to WZB117.
- #12 showed synergistic anticancer activity when combined with metformin in SKOV3 ovarian cancer cells.
Conclusions:
- Identified potential GLUT1 inhibitors with moderate anticancer effects.
- Compound #12 is a promising candidate for further development, particularly for enhancing metformin efficacy in ovarian cancer.
- Targeting GLUT1 presents a viable strategy for combination cancer therapy.
