Introduction: The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. Methods: Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. Results: In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. Conclusion: mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

中文翻译：

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VEGF165b突变体通过诱导肿瘤血管成熟促进紫杉醇诱导的小鼠乳腺癌细胞凋亡

简介：本实验室研发的抗血管生成剂血管内皮生长因子165b（VEGF165b）突变体（mVEGF165b），具有优于天然VEGF165b的抗肿瘤活性；然而，其作用机制和成药性还需要进一步探索。方法：以商品化抗血管生成药物贝伐珠单抗作为阳性对照，对mVEGF165b的作用机制和可开发性进行评估和探索。采用 Cell Counting Kit-8 检测评估 mVEGF165b 和贝伐珠单抗单独对人脐静脉内皮细胞 (HUVEC) 增殖的影响。同时，评估了mVEGF165b和贝伐珠单抗联合紫杉醇对乳腺癌小鼠模型的抑制作用。采用免疫组织化学方法检测其对肿瘤血管成熟的影响，采用末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）法检测肿瘤细胞的凋亡情况。结果：体外细胞实验证实mVEGF165b抑制HUVECs增殖，功效与贝伐珠单抗相当。mVEGF165b和贝伐珠单抗联合紫杉醇显着延缓小鼠乳腺癌的生长。免疫组织化学和TUNEL检测显示，mVEGF165b和贝伐珠单抗联合紫杉醇比单独紫杉醇诱导更高的血管成熟度和更多的细胞凋亡。结论：mVEGF165b表现出与贝伐珠单抗相似的疗效和作用机制，表明其有潜力开发成安全有效的抗血管生成药物。