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

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.
AuthorsMacus Tien Kuo, Niramol Savaraj, Lynn G Feun
JournalOncotarget (Oncotarget) Vol. 1 Issue 4 Pg. 246-51 (Aug 2010) ISSN: 1949-2553 [Electronic] United States
PMID21152246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)
Chemical References
  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • SP4 protein, human
  • Sp4 Transcription Factor
  • Polyethylene Glycols
  • Arginine
  • Hydrolases
  • Arginase
  • ADI PEG20
  • arginine deiminase
  • Argininosuccinate Synthase
  • Antineoplastic Agents (therapeutic use)
  • Arginase (metabolism)
  • Arginine (deficiency, metabolism)
  • Argininosuccinate Synthase (genetics, metabolism)
  • Autophagy (drug effects)
  • Gene Expression Regulation, Neoplastic
  • Genes, myc
  • Humans
  • Hydrolases (pharmacology, therapeutic use)
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Molecular Targeted Therapy
  • Neoplasms (drug therapy, metabolism)
  • Polyethylene Glycols (pharmacology, therapeutic use)
  • Sp4 Transcription Factor (genetics, metabolism)

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