Roles of nitric oxide and polyamines in brain tumor growth

Nitric oxide (NO) and polyamines: putrescine, spermidine and spermine, are key arginine metabolites in mammalian tissues that play critical roles i.a. in regulation of vascular tone (NO), and cell cycle regulation (polyamines). In the brain, both classes of molecules additionally have neuromodulatory and neuroprotective potential, and NO also a neurotoxic potential. Here we review evidence that brain tumors use the NO- and polyamine-synthesizing machineries to the benefit of their differentiation and growth from healthy glia and neurons. With a few exceptions, brain tumors show increased activities of one or all of the three arginine (Arg) to NO-converting nitric oxide synthase (NOS) isoforms (iNOS, eNOS, nNOS), but also elevated activities of polyamines-generating and modifying enzymes: arginase I/II, ornithine decarboxylase and spermidine/spermine N¹-acetyltransferase. The degree of stimulation of NO- and polyamine synthesis often correlates with brain tumor malignancy. Excess NO, but also spermine, spermidine and their N¹-acetylated forms, are tumor- and context-dependently involved in angiogenesis, tumor initiation and growth, and resistance to chemo- or radiotherapy. Hypothetically, increased demand for NO and/or polyamines is likely to contribute to Arg auxotrophy of malignant brain tumors, albeit the causal nexus awaits experimental verification.