The gold standard of treatment for advanced hormone-sensitive prostate cancer (PC) has been androgen deprivation therapy (ADT), but tumors always acquire resistance, leading to castrate-resistant PC. Apoptosis and cell death are part of the cancer cells’ immediate reaction to ADT. However, a significant portion is halted but still alive. In order to identify possible metabolic targets for therapy, researchers heavily characterized the early metabolic alterations that occur following ADT in the study.
Multiple PC cell lines with varying hormone response status, including the ADT-sensitive lines LNCaP and VCaP and the resistant C4-2 and DU145, were used to characterize and block metabolic pathways over a period of days using a combination of mass spectrometry, optical metabolic imaging, oxygen consumption rate, and protein expression analysis.
Several glycolytic intermediates were present after ADT, according to mass spectrometry examination of LNCaP before and after exposure. After ADT, there was an immediate decrease in the rate of extracellular acidification, a decrease in the optical redox ratio [NAD(P)H/FAD], and a downregulation of important regulatory enzymes for fatty acid and glutamine consumption. The optical redox ratio found with ADT alone in LNCaP and VCaP was reversed by inhibiting fatty acid oxidation and synthesis, it was discovered through the screening of numerous metabolic inhibitors. However, after exposure to ADT, both cell lines showed enhanced sensitivity to the glycolytic inhibitor 2-Deoxy-D-glucose(2-DG) and retained sensitivity to the inhibitor of the electron transport chain Malonate. Synergistic cell death is produced by the injection of 2-DG after ADT, as opposed to simultaneous administration.
Early on following ADT, hormone-sensitive PC cells showed changed metabolic profiles, such as a generalized decrease in energy consumption, a quiescent/senescent phenotype, and susceptibility to certain metabolic inhibitors. Following ADT, glycolytic inhibiting medications (such as 2-DG) may show promise.
Reference: onlinelibrary.wiley.com/doi/10.1002/pros.24428
