Effects of Lactate Transport Inhibition by AZD3965 in Muscle-Invasive Urothelial Bladder Cancer

Abstract

The Warburg Effect is characterized by high rates of glucose uptake and lactate production. Monocarboxylate transporters (MCTs) are crucial to avoid cellular acidosis by internal lactate accumulation, being largely overexpressed by cancer cells and associated with cancer aggressiveness. The MCT1-specific inhibitor AZD3965 has shown encouraging results in different cancer models. However, it has not been tested in urothelial bladder cancer (UBC), a neoplasm where rates of recurrence, progression and platinum-based resistance are generally elevated. We used two muscle-invasive UBC cell lines to study AZD3965 activity regarding lactate production, UBC cells’ viability and proliferation, cell cycle profile, and migration and invasion properties. An “in vivo” assay with the chick chorioallantoic membrane model was additionally performed, as well as the combination of the compound with cisplatin. AZD3965 demonstrated anticancer activity upon low levels of MCT4, while a general lack of sensitivity was observed under MCT4 high expression. Cell viability, proliferation and migration were reduced, cell cycle was arrested, and tumor growth “in vivo” was inhibited. The compound sensitized these MCT4-low-expressing cells to cisplatin. Thus, AZD3965 seems to display anticancer properties in UBC under a low MCT4-expression setting, but additional studies are necessary to confirm AZD3965 activity in this cancer model.

Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect

“…Theoretically, HT1376R cells should be able to compensate for MCT4 absence with MCT1 presence and, therefore, lactate exportation is assured. Of note, in a previous work where we used these low-MCT4-expressing HT1376R cells together with another cell line showing higher levels of the MCT4 (253J cell line, anticancer activity and re-sensitization to cisplatin upon MCT1 inhibition was largely dependent on the lack of MCT4 expression [51], which corroborated the interchangeable roles of the transporters [59] and underpinned the importance of MCT1 on lactate exportation in HT1376R cells.…”

“…Thus, the Seahorse results support the occurrence of an exacerbated glycolytic phenotype in the CR cells. HT1376R cells were also used by our group in previous works, in which a resensitization to cisplatin was observed upon depletion of glucose uptake or lactate transport through pharmacological treatment with the HK2 inhibitor 2-deoxy-D-glucose [24] or with the MCT1 specific inhibitor AZD3965 [51], respectively. These results corroborate previous findings of the preponderance of the glycolytic metabolism in a CR setting in bladder cancer [23,26,30,33].…”