Abstract A60: Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism

Abstract

Abstract The tendency of cancer cells to have enhanced rates of glycolysis presents a target for combination therapy with agents that affect glucose metabolism. We have explored the action of three compounds on a panel of eight human bladder cancer cell lines showing a spectrum of growth rates. The compounds were an inhibitor of PFKFB3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), an inhibitor of pyruvate dehydrogenase kinase, dichloroacetate, and, paradoxically, phenformin. The biguanide phenformin increases glucose metabolism in some cancer cell lines but it can also be growth inhibitory. Effects on glucose metabolism and lactic acid production were monitored respectively by an enzyme-linked colorimetric assay for glucose in the medium and changes in the pH of the medium reflected by the absorbance of phenol red at 560 nm. Changes in these parameters were most marked for the rapidly growing T24 and UM-UC-3 bladder cancer cells and generally showed parallel changes with control and treated cells. We had previously established growth inhibitory effects of 10µM 3PO on the eight bladder cancer cell lines monitored by staining with sulforhodamine B. Inhibitory effects of 2.5 mM dichloracetate have been observed with additive inhibitory effects when cells were treated with combinations of 3PO and dichloracetate. Effects of phenformin as a single agent were studied at 10, 25 and 50µM. Concentration-related increases in medium acidification and glucose uptake were most consistently seen with T24 cells. The effects with 50µM phenformin could be blocked by coincubation with 2.5 mM dichloracetate. On the other hand, additive inhibitory effects on growth may be observed with combinations of phenformin and dichloroacetate. Sensitivity to the actions of phenformin could not be simply related to growth rate. The T24 and UM-UC-3 cells have similar growth rates and had similar inhibitory effects on growth when treated with phenformin. However, medium acidification and glucose uptake were less affected in the UM-UC-3 cells. Although there are conditions in which phenformin appears to increase the Warburg effect as it relates to glucose metabolism, there can be additive growth inhibitory effects when bladder cancer cells are treated with phenformin in combination with agents that inhibit glucose metabolism. Citation Format: Michael A. Lea, Mansour Altayyar, Charles desBordes. Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A60.