A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism

• DOI: 10.1186/s40170-021-00248-7
• Publication Date: 2021-03-26T14:02:52Z
• Authors: Pratik Shriwas; Dennis Roberts; Yunsheng Li; Liyi Wang; Yanrong Qian; Stephen Bergmeier; Jennifer Hines; Subhodip Adhicary; Corinne Nielsen; Xiaozhuo Chen
• Keywords: Carbohydrate Metabolism

Abstract Background Cancer cells drastically increase the uptake of glucose and metabolism by overexpressing class I transporters (GLUT1-4) to meet their energy biomass synthesis needs are very sensitive vulnerable deprivation. Although targeting via GLUTs has been an attractive anticancer strategy, relative efficacy multi-GLUT or single GLUT is unclear. Here, we report DRB18, a synthetic small molecule, potent compound whose pan-class inhibition superior targeting. Methods Glucose MTT/resazurin assays were used measure DRB18’s inhibitory activities transport cell viability/proliferation in human lung cancer other lines. Four HEK293 lines expressing GLUT1-4 individually determine IC 50 values activity transport. Docking studies performed investigate potential direct interaction DRB18 with GLUT1-4. Metabolomics analysis was identify metabolite changes A549 treated DRB18. treat tumor-bearing nude mice. The GLUT1 gene knocked out how KO affected tumor growth. Results reduced mediated each different s, which match docking glidescores correlation coefficient 0.858. revealed that altered energy-related changing abundance metabolites glucose-related pathways vitro vivo. eventually led G1/S phase arrest increased oxidative stress necrotic death. IP injection mice at 10 mg/kg body weight thrice week significant reduction volume compared mock-treated tumors. In contrast, knockout did not reduce volume. Conclusions inhibitor vivo cells. Mechanistically, it likely bind outward open conformation GLUT1-4, reducing growth through inhibiting GLUT1-4-mediated metabolisms. Pan-class better strategy than for