MnSOD模拟化合物及其配体联合药物抗肿瘤作用研究

Mimics of manganese superoxide dismutase(MnSODm) is a new synthetic drug by Lanzhou University. We obtained National Natural Science Foundation in 2010, and the studies of this foundation confirmed that MnSODm has significant anti-lymphoma effect in vivo and in vitro. In addition, our preliminary experiments confirmed that its ligand also has significant anti-tumor effect, so we think that its ligand may have a major anti-tumor activity structure. So far, we do not know whether the MnSODm and its ligand have anti-tumor effect on the other common solid tumors， and the anti-tumor efficacy differences between MnSODm and its ligand is not clear. The aim of this study is to observe the anti-tumor effects of MnSODm and its ligand combined with chemotherapy drugs or targeted drugs respectively on solid tumor cells and its possible mechanism. These solid tumers contain lung cancer, gastric cancer，liver cancer, and colorectal cancer. The present study consists of six parts: .1..Studies on antitumor effects of MnSODm and its ligand on solid tumor cell lines in vitro comparative study..2..The evaluation of effects of MnSODm and its ligand in combination with chemotherapy drugs against tumors in vitro comparative study. .3..The evaluation of effects of MnSODm and its ligand in combination with targeted drugs against tumors in comparative study in vitro..4..Studies on antitumor effects of MnSODm and its ligand on solid tumor cell lines in nude mice tumor transplantation test in vivo..5..The investigation of some changes in bone marrow function, blood, biochemical liver and kidney function in vivo nude mice treated with MnSODm and its ligand..6..The studies on its potential mechanisms of MnSODm and its ligand in solid tumors..These studies will provide experimental and theoretical basis for the development of new efficient MnSODm analogues with antitumor effect and the clinical use of them in solid tumors.

前期我们的国家自然基金项目研究证实兰州大学新合成的锰超氧化物歧化酶模拟化合物（MnSODm)具有显著体内外抗淋巴瘤作用，最近我们的预实验又证实其配体也有显著抗肿瘤作用，说明其配体可能有主要抗肿瘤活性结构。MnSODm及配体在实体肿瘤的作用及其抗肿瘤效果的差异均不明确。本项目旨在研究MnSODm及配体联合化疗药物、靶向药物抗实体肿瘤作用及机制，研究对象为肺癌、胃癌、肝癌、结肠癌。项目分为六部分①MnSODm及配体对多种实体瘤细胞株体外抗肿瘤作用对照研究。②MnSODm及配体联合化疗药物抗肿瘤作用体外对照研究。③ MnSODm及配体联合靶向药物抗肿瘤作用体外对照研究。④MnSODm及配体对实体瘤体内裸鼠实验对照研究。⑤MnSODm及配体对骨髓功能、血常规、肝肾功能的影响。⑥MnSODm及配体抗肿瘤机制研究。通过研究为开发高效新型MnSODm抗肿瘤类似物并广泛应用于实体肿瘤提供实验和理论依据。

本项目旨在MnSODm及配体(N1,N3-bis(3-methoxysalicylidene) diethylenetriamine，Valdien)对常见实体肿瘤的抗肿瘤作用及机制，并观察二者与常见化疗药物、靶向药物的联合作用。项目通过体内外实验发现MnSODm及配体对常见的实体瘤具有抗肿瘤作用，裸鼠动物实验显示副作用轻微，MnSODm的作用强于配体。多种实体瘤细胞体外实验中，MnSODm及配体与大多数化疗药物未显示协同作用。MnSODm及配体抗肿瘤细胞增殖、诱导凋亡与NF-κB核转位调控PI3K/Akt通路激活Caspase级联激活有关。在体外对肠癌细胞的研究中则显示MnSODm配体(Valdien)可通过调节cyclinD1、p21、Bcl-xL、survivin、Bcl-2、Bax的表达产生作用，抑制Wnt1/β‐catenin信号通路产生抗肿瘤作用是其可能的作用机制之一。体内动物实验采用裸鼠异种移植瘤模型也显示了MnSODm及配体的抗肿瘤作用。通过上述研究为开发具有抗肿瘤作用的MnSODm类似物提供了实验和理论依据。