TRAIL-FeSOD与Nutlin3联合用药选择性抑制肿瘤细胞增殖

Nutlin3, a small-molecule agonist of p53, is currently in phase II clinical trials for cancer treatment. Despite promising effects of Nutlin3 on p53 induction in laboratory studies and initial clinic treatments, Nutlin3 alone only caused modest reactivation of p53 in some wild-type p53-expressing cells such as malignant melanomas; in addition,its effects on normal tissues and cell types remain largely to be determined. Like most other drugs employed in cancer therapy, it is unlikely that Nutlin3 will be used as a monotherapy. Drugs that can selectively target cancer cells as well as cooperate with the p53 pathway are thus greatly needed. Iron-superoxide dismutase (Fe-SOD) is a potential candidate as it selectively inhibits cancer cells by eliminating the abnormally high levels of reactive oxygen species (ROS) in cancer cells. Our previous studies have shown that Fe-SOD cooperated with Nutlin3 to selectively inhibit cancer cells in vitro and in vivo,to overcome some disadvantages of Nutlin3 treatment. However, Fe-SOD also has some critical disadvantages in clinical application (non-specific cancer cell targeting; large molecular weight interferes with its ability to permeate the cellmembrane). It has been confirmed that a novel fusion protein TRAIL-FeSOD both have identification of tumor cell targeting and cell membrane penetration ability of TRAIL; and function of FeSOD that clear excess ROS in tumor cells; in addition, TRAIL-FeSOD exhibits synergistic apoptotic effects on cancer cells and demonstrates minimal toxicity to normal cells. In theory, co-treatment of Fe-SOD and Nutlin3 will overcome both clinical disadvantages of Fe-SOD, enhance therapeutic effect of Nutlin3.

Nutlin3，是一种小分子量的p53激活剂，处于II期肿瘤治疗临床研究，研究表明一些肿瘤细胞对其有耐受性，其对正常细胞也有潜在危害；因此，能够协同p53途径、并选择性抑制肿瘤增殖的药物是值得研究的。Fe-SOD能够有效地清除肿瘤细胞内过多的ROS，选择性抑制肿瘤细胞增殖。我们先前研究表明: Fe-SOD与Nutlin3的联合用药能够有效地增强Nutlin3的治疗效果。但Fe-SOD对肿瘤细胞缺乏识别能力，分子量大难以穿透细胞膜，这些缺陷限制了其临床应用。前期研究我们构建表达融合蛋白TRAIL-FeSOD，其被证实具有TRAIL靶向识别肿瘤表面抗原后能引导蛋白内吞的能力，以及Fe-SOD清除细胞内ROS功能，两者协同作用从而达到靶向杀死肿瘤细胞，降低对正常细胞危害的效果。本研究将TRAIL-FeSOD取代Fe-SOD与Nutlin3联合用药，克服Fe-SOD的缺陷，提高治疗效果。

Nutlin3，是一种小分子量的p53激活剂，处于II期肿瘤治疗临床研究，研究表明一些肿瘤细胞对其有耐受性，其对正常细胞也有潜在危害；因此，能够协同p53途径、并选择性抑制肿瘤增殖的药物是值得研究的。Fe-SOD能够有效地清除肿瘤细胞内过多的ROS，选择性抑制肿瘤细胞增殖。我们先前研究表明: Fe-SOD与Nutlin3的联合用药能够有效地增强Nutlin3的治疗效果。但Fe-SOD对肿瘤细胞缺乏识别能力，分子量大难以穿透细胞膜，这些缺陷限制了其临床应用。前期研究我们构建表达融合蛋白TRAIL-FeSOD，其被证实具有TRAIL靶向识别肿瘤表面抗原后能引导蛋白内吞的能力，以及Fe-SOD清除细胞内ROS功能，两者协同作用从而达到靶向杀死肿瘤细胞，降低对正常细胞危害的效果。本研究将TRAIL-FeSOD取代Fe-SOD与Nutlin3联合用药，克服Fe-SOD的缺陷，提高治疗效果。我们的研究表明：TRAIL-FeSOD与Nutlin3联合用药能够有效地增强Nutlin3的治疗肿瘤细胞，特别是Nutlin3耐受性肿瘤细胞的效果，但对正常细胞的影响很小，而这过程与p27蛋白的激活有关。进一步的体内实验证明：在Nutlin3耐受性肿瘤细胞B16细胞移植构建的肿瘤小鼠模型研究中，TRAIL-FeSOD与Nutlin3联合用药的治疗效果比其单独治疗效果更加显著。因此，我们的研究表明TRAIL-FeSOD与Nutlin3的联合用药在体外和体内实验中都展现出很好的协同效果，增强了Nutlin3耐受性肿瘤细胞的敏感性，同时对正常组织细胞没有显著的毒副作用。