title: Anti-tumor efficacy of a recombinant human arginase in human hepatocellular carcinoma.
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.
authors.affiliation: Department of Surgery, The University of Hong Kong Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Ariel K M
authors.initials: AK
authors.lastname: Chow
authors.forename: Lui
authors.initials: L
authors.lastname: Ng
authors.forename: Hung
authors.initials: H
authors.lastname: Sing Li
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Cheng
authors.forename: Colin S C
authors.initials: CS
authors.lastname: Lam
authors.forename: Thomas C C
authors.initials: TC
authors.lastname: Yau
authors.forename: Paul N M
authors.initials: PN
authors.lastname: Cheng
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Roberta W C
authors.initials: RW
authors.lastname: Pang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001119:Arginase / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058990:Molecular Targeted Therapy; D011994:Recombinant Proteins / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D001119:Arginase