Anti-tumor Efficacy of a Recombinant Human Arginase in Human Hepatocellular Carcinoma

Author(s): Ariel K.M. Chow, Lui Ng, Hung Sing Li, Chi Wai Cheng, Colin S.C. Lam, Thomas C.C. Yau, Paul N.M. Cheng, Sheung Tat Fan, Ronnie T.P. Poon, Roberta W.C. Pang.

Journal Name: Current Cancer Drug Targets

Volume 12 , Issue 9 , 2012

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Abstract:

Hepatocellular carcinoma (HCC) is considered as auxotrophic for arginine and BCT-100, a new recombinant human arginase, has been synthesized for arginine deprivation to inhibit arginine-dependent tumor growth. The aim of the present study was to evaluate the effects of BCT-100 on the inhibition of in vitro cell proliferation of HCC cell lines and in vivo tumor growth. The molecular mechanism involved was also studied. The anti-tumor efficacy of BCT-100 on cell proliferation, cell cycle distribution and cellular apoptosis were determined in human hepatoma HepG2 and PLC/PRF/5 cells. Protein expression in the Wnt/β-catenin and Akt signaling pathways were analyzed by western blotting. Tumors were also established subcutaneously and BCT-100, in combination with oxaliplatin, was administrated i.p. to study the anti-tumor growth of the drugs. Treatment with BCT-100 was found to inhibit cell proliferation and enhance caspasedependent cellular apoptosis. Cell cycle arrest at S phase was observed. Inhibition of Wnt/β-catenin and Akt signaling pathways, with a reduction in survivin and XIAP protein expressions, were also observed. Furthermore, combined treatment of BCT-100 and chemotherapy with oxaliplatin demonstrated synergistic inhibiting effect on tumor growth and the overall survival probability was enhanced as compared with BCT-100 or oxaliplatin treatment alone. These preclinical data demonstrate robust anti-tumor activity of BCT100 in HCC, thus providing the basis for its exploitation as a potential therapeutic agent in arginine-driven tumors. The positive effect of testing BCT100 with oxaliplatin in PLC/PRF/5 tumours also supports the rationale of combining BCT-100 and oxaliplatin in the clinical treatment of HCC.

Keywords: Hepatocellular carcinoma, human recombinant arginase, novel therapy, preclinical study, survivin, Wnt/β-catenin signaling pathway, XIAP, polyethylene glycol, propodium iodide, ornithine transcarbamylase, "3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide", mammalian target of rapamycin, mitogen-activated protein kinase, low-density-lipoprotein receptor protein, eukaryotic translation initiation factor 4E, dishevelled (dsh) homolog

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Article Details

VOLUME: 12
ISSUE: 9
Year: 2012
Page: [1233 - 1243]
Pages: 11
DOI: 10.2174/15680096112091233
Price: $58

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