+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Cancers 11(2)

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 066446181

Download citation: RISBibTeXText

PMID: 30704052

DOI: 10.3390/cancers11020156

Related references

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform. Plos One 11(12): E0168366, 2017

Characterization of Hit Compounds Identified from High-throughput Screening for their Effect on Blood-brain Barrier Integrity and Amyloid-β Clearance: In Vitro and In Vivo Studies. Neuroscience 379: 269-280, 2018

An in vivo high-throughput screening approach targeting the type IV secretion system component VirB8 identified inhibitors of Brucella abortus 2308 proliferation. Infection and Immunity 79(3): 1033-1043, 2011

SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. Journal of Biomolecular Screening 11(8): 959-967, 2006

New inhibitors of ABCG2 identified by high-throughput screening. Molecular Cancer Therapeutics 6(12 Pt 1): 3271-3278, 2007

A class of allosteric caspase inhibitors identified by high-throughput screening. Molecular Cell 47(4): 585-595, 2013

A high-throughput screening of kinase inhibitors identifies a regulatory role of VEGF signaling for transendothelial transport of high-density lipoproteins. Atherosclerosis 252: E199-E200, 2016

IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. Plos One 7(4): E35792, 2012

Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening. Journal of Medicinal Chemistry 49(17): 5232-5244, 2006

Novel Scaffolds of Cell-Active Histone Demethylase Inhibitors Identified from High-Throughput Screening. Journal of Biomolecular Screening 20(6): 821-827, 2016

Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State. Cell Chemical Biology 25(11): 1389-1402.E9, 2018

Inhibitors of Difficult Proteina Protein Interactions Identified by High-Throughput Screening of Multiprotein Complexes. 2013

Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography. Antimicrobial Agents and ChemoTherapy 51(11): 3915-3923, 2007

Small-molecule inhibitors of phosphatidylcholine transfer protein/StarD2 identified by high-throughput screening. Analytical Biochemistry 383(1): 85-92, 2008

Nonspecific enhancement of gene expression by compounds identified in high-throughput cell-based screening. Biotechniques 37(1): 120-122, 2004