HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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.
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
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: