Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest

T. L. Lam, G. K.Y. Wong, H. C. Chong, P. N.M. Cheng, S. C. Choi, T. L. Chow, S. Y. Kwok, R. T.P. Poon, D. N. Wheatley, Wai Hung Lo, Yun Chung Leung

Research output: Journal article publicationJournal articleAcademic researchpeer-review

58 Citations (Scopus)

Abstract

Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G2/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.
Original languageEnglish
Pages (from-to)91-100
Number of pages10
JournalCancer Letters
Volume277
Issue number1
DOIs
Publication statusPublished - 8 May 2009

Keywords

  • Combination therapy
  • G /M phase arrest 2
  • Hepatocellular carcinoma (HCC)
  • Ornithine transcarbamylase
  • Recombinant human arginase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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