Журнал клинической токсикологии
Открытый доступ

Абстрактный

Effects of Selected Inhibitors of Protein Kinases and Phosphatases on Cellular Respiration: An In Vitro Study

Saeeda Almarzooqi, Alia Albawardi, Ali S. Alfazari, Dhanya Saraswathiamma, Hidaya Mohammed Abdul-Kader, Sami Shaban, Robert Mallon and Abdul-Kader Souid

Inhibitors of protein kinases/phosphatases are known to alter cellular metabolism. Effects of these rapidly identified small molecules on cellular respiration (mitochondrial O2 consumption) have not been adequately investigated, especially in healthy organs. This in vitro study measured cellular respiration in tissues from C57BL/6 mice with and without GSK2126458 (PI3K/mTOR inhibitor), BEZ235 (PI3K/mTOR inhibitor), GDC0980 (PI3K/mTOR inhibitor), GSK1120212 (trametinib, MEK inhibitor), sorafenib, regorafenib (multikinase inhibitors), and cyclosporine (calcineurin inhibitor). Cellular respiration was measured by the phosphorescence oxygen analyzer, aided by the O2 probe Pd(II)-meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. Cyanide inhibited O2 consumption, confirming the oxidation occurred in the respiratory chain. Renal cellular respiration decreased 26-34% in the presence of 10 μM GSK2126458 (p<0.001), 10 μM BEZ235 (p<0.001), or 1.0 μM GDC0980 (p<0.001). Liver cellular respiration decreased 20-32% with 10 μM GSK2126458 (p=0.048), 0.1 μM BEZ235 (p=0.028), or 0.1 μM GDC0980 (p=0.016). Heart cellular respiration decreased 19-27% with 10 μM GSK2126458 (p=0.078), 10 μM BEZ235 (p=0.040), or 10 μM GDC0980 (p=0.036). GSK1120212, sorafenib, regorafenib, and cyclosporine had no effects on cellular respiration. Thus, cellular bioenergetics (the biochemical processes involved in energy conversion) is interconnected with PI3K/PTEN/Akt/mTOR; and inhibitors of this cascade impair cellular respiration. This biomarker (cellular respiration) senses the activity/toxicity of this class of molecularly targeted agents.