A novel pan class-I glucose transporter inhibitor DRB18 exhibits synergistic effects with paclitaxel in vitro and in vivo against human non-small cell lung cancer
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Background
Cancer cells depend on glucose for biomass synthesis, cell proliferation, and drug resistance. Glucose transporter (GLUT) transcripts as well as proteins are upregulated in human lungs and other cancers and are negatively correlated with patient survival, particularly GLUT1 and GLUT3. Thus, inhibiting GLUT function has been an attractive anticancer strategy. We previously characterized WZB117 and DRB18, first- and second-generation pan-class I GLUT inhibitors, respectively. DRB18 strongly inhibits glucose transport mediated by GLUT1-4 in non-small lung cancer (NSCLC) A549 cells in vitro and in vivo . Here, we report DRB18 as a more stable and potent anticancer compound, compared to WZB117.
Methods
Immunohistochemistry analysis was performed in Lung adenocarcinoma (LUAD) tissue array to investigate GLUT1 and GLUT3 protein expression between normal, lower and higher stage LUAD patients. Bioinformatics analysis was performed to examine additive effect of GLUT3 to GLUT1 mediated prognosis in LUAD. Glucose uptake and resazurin dye-based proliferation assays were used to determine glucose uptake inhibitory and cell proliferation inhibitory against panel of human cancer cell lines A549, Panc1 and Hela. DRB18 potency was tested against the presence of extracellular nutrients glucose, glutamine and ATP. Synergism between DRB18 and clinically approved anticancer drugs was tested against cancer cells. DRB18 and advanced NSCLC drug Paclitaxel were tested for synergy in vitro and in vivo .
Results
GLUT1/3 combination exhibited higher hazard ratio than either GLUT1 and GLUT3 alone in many cancer types including LUAD. DRB18 reduced glucose uptake in NSCLC A549, pancreatic Panc1, and cervical Hela cancer cells with varied but strong anticancer potencies in the presence or absence of extracellular nutrients such as ATP and glucose. Combined with different clinical and pre-clinical anticancer compounds such as V9302, CB839, Sutent, Brigatinib, DRB18 significantly increased death of A549 and Panc1 cells. Noteworthy, DRB18 exhibited strong anticancer synergy with paclitaxel, an approved chemo drug for NSCLC, drastically reducing cancer cell proliferation in vitro and growth of A549 tumors grafted on the flank of nude mice without significant side effects, compared to single drug treatments. Mechanistically, DRB18 treatment with paclitaxel elevated the expression of Caspases 3 and 9, suggesting GLUT-inhibiting and apoptosis-inducing anticancer mechanisms of DRB18 with paclitaxel.
Conclusions
Collectively, our results demonstrate anticancer efficacy of pan class-I GLUT inhibitor DRB18 in combination with paclitaxel, providing a potentially more efficacious therapeutic strategy for treating advanced NSCLC and other cancers.
