L-Arginine metabolism alteration by L-Lysine intervention increased cell death in triple negative breast cancer cell

Abstract Background L-Arginine effectiveness cancer therapy is a matter of controversy. L-Arginine is a substrate for different metabolites influencing cancer cells. Arginase and nitric oxide synthase (NOS) are two important enzymes in the L-Arginine metabolic pathway. Nitric oxide (NO) is produced by NOS and the main products of arginase activity are polyamines. NO can decrease cancer cells viability dependent on its concentration but, polyamines shown to promote cancer cell growth/metastasis. Due to Arginase and NOS competition over L-Arginine binding, inhibition of arginase activity seems to increase NOS activity as well as NO production. Thus, the aim of the present study is to affect L-Arginine metabolic pathway through L-Lysine induced arginase inhibition in MDA-MB-231 and MDA-MB-468 Methods MDA-MB-231 and MDA-MB-468 were used as triple negative breast cancer cells with different arginase activity. Both cell lines were treated with different concentrations of L-Arginine and L-Lysine. Cell viability was assessed by MTT assay 24 and 48h after treatment. Arginase activity, ROS level and NO concentration was examined. Cell cycle was assessed using flowcytometry. Real-time PCR was performed to assess apoptotic and metabolic genes expression Results Our results indicated that cell viability and arginase activity were decreased in MDA-MB-468 with high arginase level more than MDA-MB-231 and studying the cell cycle also showed G2/M arrest in both cell lines following combination treatment with L-Lysine with L-Arginine. L-Lysine treatment resulted in increased apoptotic genes and decreased metabolic related genes expression in both cell lines Conclusion Altogether, our findings indicated that alternation in L-Arginine metabolic pathway using L-Lysine causes higher NO concentration which consequently increases cell death in triple negative breast cancer cells with different arginase level, which in turn can increase L-Arginine effect on cell lines with higher arginase activity