title: Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes.
abstract: 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 down-regulates 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.
authors.affiliation: Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, USA. tkuo@mdanderson.org
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000172:deficiency / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D051706:Sp4 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497124:SP4 protein, human; D051706:Sp4 Transcription Factor; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; D001119:Arginase; C512527:ADI PEG20; C019723:arginine deiminase; D001124:Argininosuccinate Synthase