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Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes

2010; Impact Journals LLC; Volume: 1; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.135

1949-2553

Macus Tien Kuo, Niramol Savaraj, Lynn G. Feun,

Virus-based gene therapy research

It has been shown that a subset of human cancers, notably, melanoma and hepatocellular carcinoma (HCC) are auxotrophic for arginine (Arg), because they do not express argininosuccinate synthetase (ASS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline.These ASS-negative cancer cells require Arg from extracellular sources for survival.When they are exposed to recombinant Arg-degrading enzymes, e.g.arginine deiminase (ADI) or arginase, they die because of Arg starvation; whereas normal cells which express ASS are able to survive.A pegylated ADI (ADI-PEG20) has been developed for clinical trials for advanced melanoma and HCC; and favorable results have been obtained.ADI-PEG20 treatment induces autophagy in auxotrophic cancer cells leading to cell death.Clinical studies in melanoma patients show that re-expression of ASS is associated with ADI-PEG20 resistance.ADI-PEG20 treatment downregulates the expression of HIF-1α but up-regulates c-Myc in culture melanoma cells.Induction of ASS by ADI-PEG20 involves positive regulators c-Myc and Sp4 and negative regulator HIF1α.Since both HIF-1α and c-Myc play important roles in cancer cell energy metabolism, together these results suggest that targeted cancer cell metabolism through modulation of HIF-1α and c-Myc expression may improve the efficacy of ADI-PEG20 in treating Arg auxotrophic tumors.