Using the extra cellular flux analyzer (Agilent Seahorse platform), they characterized cell lines based on their metabolic parameters, extracellular acidification rates (ECAR) and oxygen consumption rates (OCR), and determined whether they relied on glycolysis or oxidative phosphorylation relative to each other. Novel LDH inhibitors were tested in these cell lines for their effects on proliferation, invasion, and migration. These inhibitors were also tested on xenograft tumors either as a single agent or in combination with metformin. In a separate project, they evaluated the effect of NAMPT inhibitors as single agents in cell lines and flank xenografts using similar methodology.
Most bladder cancer cell lines depend on oxidative phosphorylation to some degree (based on high OCR) but a few are reliant on glycolysis (based on high ECAR). The more glycolytic cell lines were more sensitive to LDH inhibition; however, the other cell lines responded to LDH inhibition when made more glycolytic by either hypoxia or by cotreatment with metformin. The UMUC3 xenograft demonstrated decreased growth with LDH inhibition. Although NAMPT inhibition was only successful in a few bladder cancer cell lines, it was extremely potent in these cell lines. NAPRT (an enzyme involved in the repletion of NAD levels from nicotinic acid) deficient cell lines were sensitive to NAMPT inhibitor, whereas the cells with higher expression of NAPRT were resistant. In the UMUC3 flank xenograft, NAMPT inhibition was effective in inhibiting tumor growth.
In conclusion, these data describe the metabolic phenotype of bladder cancer cell lines and demonstrates that LDH inhibition in combination with metformin can be effective in inhibiting tumor growth in bladder cancer cell lines. NAMPT inhibition is more potent but only NAPRT deficient cell lines are sensitive
Presented by: Piyush K. Agarwal, M.D, National Cancer Institute, National Institutes of Health
Written by: Stephen B. Williams, M.D., Associate Professor, Division of Urology, The University of Texas Medical Branch, Galveston, TX. and Ashish M. Kamat, M.D. Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 16th Annual Meeting of the International Bladder Cancer Network (IBCN) October 11-13, 2018 - the Inntel Hotels Rotterdam Centre, Rotterdam, The Netherlands