Department of Surgery, The University of Hong Kong Queen Mary Hospital, Pokfulam, Hong Kong.
Curr Cancer Drug Targets. 2012 Nov 1;12(9):1233-43. doi: 10.2174/156800912803988002.
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.
肝细胞癌（HCC）被认为是精氨酸的营养缺陷型，因此合成了新型重组人精氨酸酶 BCT-100 以剥夺精氨酸，从而抑制依赖精氨酸的肿瘤生长。本研究旨在评估 BCT-100 对体外 HCC 细胞系增殖和体内肿瘤生长的抑制作用，并研究其涉及的分子机制。在人肝癌 HepG2 和 PLC/PRF/5 细胞中，测定 BCT-100 对细胞增殖、细胞周期分布和细胞凋亡的抗肿瘤作用。通过 Western blot 分析 Wnt/β-catenin 和 Akt 信号通路中的蛋白表达。还建立了皮下肿瘤，并给予 BCT-100 联合奥沙利铂腹腔内给药，以研究药物的抗肿瘤生长作用。研究发现，BCT-100 处理可抑制细胞增殖并增强 caspase 依赖性细胞凋亡。观察到细胞周期停滞在 S 期。还观察到抑制 Wnt/β-catenin 和 Akt 信号通路，降低 survivin 和 XIAP 蛋白表达。此外，与单独使用 BCT-100 或奥沙利铂相比，BCT-100 与化疗药物奥沙利铂联合治疗对肿瘤生长具有协同抑制作用，并且整体生存概率得到提高。这些临床前数据表明，BCT100 在 HCC 中具有强大的抗肿瘤活性，为其作为潜在治疗剂在精氨酸驱动的肿瘤中的开发提供了依据。在 PLC/PRF/5 肿瘤中联合检测 BCT100 和奥沙利铂的积极效果也支持了在 HCC 的临床治疗中联合使用 BCT-100 和奥沙利铂的原理。
