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Open AccessArticle

High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo

1
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
2
The National Institute for Biotechnology in the Negev, Beer Sheva 84105, Israel
3
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
4
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Cancers 2019, 11(2), 156; https://doi.org/10.3390/cancers11020156
Received: 27 December 2018 / Revised: 17 January 2019 / Accepted: 28 January 2019 / Published: 30 January 2019
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms can thus serve as a new therapeutic strategy in oncology. As such, we sought to identify small-molecule inhibitors which sensitize tumor cells to glucose starvation by high-throughput drug screening in vitro. Specifically, we searched for inhibitors that selectively killed tumor cells growing in glucose-free but not in normal medium. This phenotypic drug screen of 7000 agents with MCF7 cells led to the identification of 67 potential candidates, 31 of which were validated individually. Among the identified compounds, we found a high number of compounds known to target mitochondria. The efficacies of two of the identified compounds, QNZ (EVP4593) and papaverine, were validated in four different tumor cell lines. We found that these agents inhibited the mTOR(Mechamistic\Mammilian Target of Rapamycin) pathway in tumor cells growing under glucose starvation, but not under normal conditions. The results were validated and confirmed in vivo, with QNZ and papaverine exhibiting superior antitumor activity in a tumor xenograft model when combined with the VEGF inhibitor bevacizumab (avastin). Administering these drug combinations (i.e., avastin and papaverine, and avastin and QNZ) led to significant reductions in proliferation and mTOR activity of the aggressive DLD1 colon cell line in mice. Given our findings, we propose that compounds targeting metabolically challenged tumors, such as inhibitors of mitochondrial activity, be considered as a therapeutic strategy in cancer. View Full-Text
Keywords: cancer metabolism; drug combination; synthetic lethality; HTS; small molecule cancer metabolism; drug combination; synthetic lethality; HTS; small molecule
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MDPI and ACS Style

Marciano, R.; Prasad, M.; Ievy, T.; Tzadok, S.; Leprivier, G.; Elkabets, M.; Rotblat, B. High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo. Cancers 2019, 11, 156.

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