Abstract
Some types of tumor cells are unable to synthesize arginine from its precursors. They exhibit growth inhibition and decreased viability in vitro and in vivo under enzymatic arginine deprivation. However, prolonged arginine starvation in human may cause vasoconstriction and thrombosis due to the deficit of arginine derivative, nitric oxide (NO), as vasodilator and disaggregant. This problem can be overcome via supplementation with exogenous NO-donors in vivo , which, in turn, may produce either, pro-apoptotic or anti-apoptotic specific effects on cancer cells under arginine restriction. In this study we elucidated the effect of exogenous NO donor, sodium nitroprusside (SNP) on the viability of human Jurkat leukemic cells under arginine deprivation in vitro . We observed that arginine deprivation suppressed cell proliferation and led to a rapid decrease in cell viability concomitant with progression of apoptosis. According to SNP IC50 determination and apoptosis assays, NO-donor at physiological concentration did not promote survival of tumor cells in arginine-free medium. Moreover, SNP cytotoxicity for Jurkat cells was increased upon arginine withdrawal, suggesting that application of NO donor in vivo may potentially enhance the therapeutic effect of arginine deprivation. Keywords: arginine deprivation, nitric oxide, sodium nitroprusside, apoptosis, leukemic cells.
Highlights
The molecular mecha nism that triggers apoptosis in tumor cells under arginine deprivation has not been yet elucidated, we recently demonstrated that alterations in arginine metabolism are not the main cause, and aberrant cell cycle regulation is most probably implicated in this process [2, 13, 18]
We studied cell growth and cell viability both in control arginine-rich medium (CM), arginine-free medium (AFM), and in AFM supplemented with metabolic precursors of arginine – citrulline and ornithine, which utilization depends on the status of arginine anabolic enzymes, ASS and OTC, respectively
We examined whether a prolonged arginine deprivation induces apoptosis in Jurkat cells that may be concomitant to the observed decrease in their viability (Fig. 1)
Summary
Human leukemic cells were demonstrated to be sensitive to arginine starvation in vitro [11]. The molecular mecha nism that triggers apoptosis in tumor cells under arginine deprivation has not been yet elucidated, we recently demonstrated that alterations in arginine metabolism are not the main cause, and aberrant cell cycle regulation is most probably implicated in this process [2, 13, 18]. In this work we aimed to elucidate whether exogenous NO donor will affect viability of human leukemic cells upon arginine deprivation, taking into account that NO was shown to elicit both pro- and antiapoptotic effects on different cell models in vitro [8, 12, 17]
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