Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice
Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice
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联合卡利他汀基因疗法和美洛昔康治疗小鼠肝细胞癌
DOI：
10.1111/j.1349-7006.2009.01306.x
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发表时间：
2009-11-01
期刊：
影响因子：
5.7
通讯作者：
Sun, Xueying
中科院分区：
文献类型：
--
作者：
Jiang, Xian;Li, Hali;Sun, Xueying
肝细胞癌（HCC）是最常见的癌症相关死亡原因之一，常规治疗效果不佳。我们以前报道过，kallistatin基因治疗通过其抗血管生成活性抑制HCC肿瘤的生长，而美洛昔康，一种选择性考克斯-2抑制剂，在体外抑制人HCC细胞的增殖并诱导凋亡。本研究的目的是确定是否联合kallistatin基因治疗和美洛昔康可以提供一个更好的治疗效果，以打击肝癌小鼠。构建激肽释放酶抑制剂表达质粒，瘤内转染后检测其表达。Kallistatin基因治疗和美洛昔康均能抑制BALB/c裸鼠皮下人HepG 2肿瘤的生长，联合治疗在抑制肿瘤生长、肿瘤血管生成和细胞增殖、增加细胞凋亡方面均优于单药治疗。基因转染可抑制肿瘤血管生成，并轻微抑制原位细胞增殖和增加细胞凋亡，但对血管内皮生长因子、碱性成纤维细胞生长因子、增殖细胞核抗原、Bcl-2、Bax的表达及caspase-3的活化无影响。美洛昔康治疗抑制细胞增殖，诱导细胞凋亡，减少增殖细胞核抗原的表达，增加caspase-3的活化，上调Bax。美洛昔康还轻微抑制肿瘤血管生成，对血管内皮生长因子或碱性成纤维细胞生长因子的表达无影响。结合两种新的抗癌药物，靶向肿瘤血管化的激肽和靶向细胞增殖和凋亡的美洛昔康，值得研究作为一种治疗策略，以打击肝癌。（Cancer Sci 2009）。
Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death, and conventional treatments offer unsatisfactory response. We have previously reported that kallistatin gene therapy suppressed the growth of HCC tumors by its anti-angiogenic activity, and meloxicam, a selective COX-2 inhibitor, inhibited proliferation and induced apoptosis of human HCC cells in vitro. The aim of this study was to determine whether combining kallistatin gene therapy and meloxicam could offer a better therapeutic effect to combat HCC in mice. A kallistatin expression plasmid was constructed and its expression was detected after intratumoral gene transfer. Both kallistatin gene therapy and meloxicam suppressed the growth of subcutaneous human HepG2 tumors established in BALB/c nude mice, and the combinational therapy showed a stronger effect in suppressing tumor growth, tumor angiogenesis and cell proliferation, and increasing cell apoptosis, than the respective monotherapies. Gene transfer of kallistatin inhibited tumor angiogenesis, and slightly inhibited cell proliferation and increased cell apoptosis in situ, but had no effect on expression of vascular endothelial growth factor, basic fibroblast growth factor, proliferating cell nuclear antigen, Bcl-2, Bax, or activation of caspase-3. Meloxicam therapy inhibited cell proliferation, induced cell apoptosis, reduced expression of proliferating cell nuclear antigen, increased activation of caspase-3, and upregulated Bax. Meloxicam also slightly inhibited tumor angiogenesis with no effect on the expression of vascular endothelial growth factor or basic fibroblast growth factor. Combining two novel anticancer agents, kallistatin targeting tumoral vascularization and meloxicam targeting cell proliferation and apoptosis, warrants investigation as a therapeutic strategy to combat HCC. (Cancer Sci 2009).