缺氧激活前药TH-302联合舒尼替尼抑制肾细胞癌体外增殖及裸鼠成瘤能力

Inhibition of hypoxia-activated prodrug TH-302 combined with sunitinib on the malignant proliferation in vitro and xenograft tumor model

目的:研究缺氧激活前药TH-302联合舒尼替尼抑制肾细胞癌(786-O细胞)体外增殖及裸鼠成瘤能力,深入探讨其分子机制。方法:采用四甲基偶氮唑蓝(MTT)比色法检测在缺氧条件下TH-302联合舒尼替尼对人肾癌786-O细胞增殖抑制率;建立786-O细胞裸鼠皮下移植瘤模型,通过免疫组化及qPCR法检测TH-302联合抑制裸鼠肿瘤生长的效果及作用机制。结果:在缺氧条件下,TH-302联合在抑制786-O细胞增殖作用中发挥协同作用;联合组可显著抑制肿瘤体积的生长,差异有统计学意义(P<0.05)。与TH-302组相比,TH-302联合舒尼替尼显著降低异种移植瘤中的缺氧区域,深入研究发现,与TH-302组相比,TH-302联合舒尼替尼组显著抑制肿瘤组织中HIF-1α,HIF-2α的表达。结论:TH-302联合舒尼替尼抑制肾癌细胞恶性增殖,减少肿瘤组织的缺氧区域,其作用机制可能与HIF-1α,HIF-2α的表达量变化有关。

OBJECTIVE To study the inhibitory effect of hypoxia-activated prodrug TH-302 combined with sunitinib on the proliferation and tumor formation of renal cell carcinoma(786-O cells) in vitro, and to explore its molecular mechanism.METHODS The inhibitory rate of TH-302 combined with sunitinib on the proliferation of human renal carcinoma 786-O cells under hypoxia was detected by MTT colorimetric assay, and the subcutaneous xenograft model of 786-O cells was established. The inhibitory effect of TH-302 combined with sunitinib on the growth of human renal carcinoma 786-O cells and its mechanism were detected by immunohistochemistry and qPCR.RESULTS Under hypoxic conditions, TH-302 combined with sunitinib played a synergistic role in inhibiting the proliferation of 786-O cells. The combined group significantly inhibited the growth of tumor tissues, and the difference was statistically significant. Compared with TH-302 group, TH-302 combined with sunitinib significantly reduced the hypoxic area in xenograft tumors. Further study found that TH-302 combined with sunitinib group significantly inhibited the expression of HIF-1α and HIF-2α in tumor tissues compared with TH-302 group.CONCLUSION TH-302 combined with sunitinib could inhibit the malignant proliferation of renal cancer cells and reduce the hypoxic area of tumor tissues, which may be related to the changes of HIF-1α and HIF-2α expression.