Tyrosine kinase inhibitor imatinib modulates the viability and apoptosis of castrate-resistant prostate cancer cells dependently on the glycolytic environment

• Published in: Life sciences (1973) 2019-02, Vol.218, p.274-283
• Main Authors: Cardoso, Henrique J., Vaz, Cátia V., Carvalho, Tiago M.A., Figueira, Marília I., Socorro, Sílvia
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Cancer; Caspase; Caspase-3; Cell culture; Cell Proliferation; Diabetes mellitus; Enrichment; Environmental effects; Enzyme inhibitors; Glucose; Glucose - metabolism; Glycaemia; Glycolysis; Glycolytic metabolism; Humans; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hyperglycemia - pathology; Hypoglycemia; Imatinib; Imatinib Mesylate - pharmacology; Inhibitors; Kinases; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Lactic Acid - metabolism; Male; Metabolism; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; Regulators; Spectrophotometry; Tumor Cells, Cultured; Tyrosine; Tyrosine kinase inhibitors
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2018.12.055

The tyrosine kinase inhibitor imatinib has been used in prostate cancer treatment with outcomes that did not follow the in vitro findings. The glycolytic environment has been shown to influence the efficacy of anti-cancer drugs. This study aimed to evaluate the effect of imatinib on cell viability, apoptosis, and metabolism in cell line models of castrate-resistant prostate cancer (CRPC) under hyperglycemic and hypoglycemic conditions. DU145 and PC3 CRPC cell lines were exposed to 20 μM imatinib under 5 mM (hypoglycemia) or 30 mM glucose (hyperglycemia) for 48–72 h. Cell viability was assessed by the MTS assay. The expression of apoptosis regulators and glycolytic metabolism-related proteins was analysed by Western blot, and the activity of caspase-3 and lactate dehydrogenase (LDH) was determined spectrophotometrically. Glucose consumption and lactate production were determined using biochemical assays. Imatinib decreased CRPC cells viability, whereas increasing apoptosis; effects only observed in hyperglycemic conditions. Glucose consumption and lactate production were significantly increased in imatinib-treated DU145 and PC3 cells, and independently of glucose availability. Accordingly, LDH expression and activity were significantly increased in response to imatinib. Higher glucose availability improved the effectiveness of imatinib suppressing survival and growth of CRPC cells. It was also shown that imatinib treatment stimulated the glycolytic metabolism of CRPC cells. This study first demonstrated that a glucose-enriched environment intensifies the effect of imatinib, which stimulates the interest for testing this compound into the clinical setting, namely in hyperglycemia conditions (diabetic patients) or in co-administration with inhibitors of glycolytic metabolism.