Yu Pengfei, Ye Liang, Wang Hongbo, Du Guangying, Zhang Jianzhao, Zhang Jinghai, Tian Jingwei
School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
Tumour Biol. 2015 Mar;36(3):2143-53. doi: 10.1007/s13277-014-2824-x. Epub 2014 Nov 15.
The purposes of this study are to investigate the antitumor activities of NSK-01105, a novel sorafenib derivative, in in vitro and in vivo models, and explore the potential mechanisms. The effects of NSK-01105 on proliferation and apoptosis of prostate cancer cells were established by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blot analysis. Two xenograft tumor models were used to verify the therapeutic effect of NSK-01105 in vivo. NSK-01105 exhibited broad-spectrum antitumor activity, particularly in prostate cancer cells. Characterization of apoptosis morphology was observed, and the percentage of apoptosis-positive cells significantly increased after NSK-01105 treatment for 24 h. Furthermore, a significant increase of the "sub-G1" population in LNCaP and PC-3 cells after NSK-01105 treatment was determined by cell cycle analysis. Tumor growth was significantly suppressed by once daily oral 30 mg/kg dose of NSK-01105 with the inhibition rates of 63.82% in LNCaP models and 64.29% in PC-3 models, respectively. The activation of Raf-1 kinase and epidermal growth factor receptor was downregulated by NSK-01105 at 10 μmol/L. Consequently, the dual inhibitions of Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways were observed by Western blot analysis. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors by inhibiting cell proliferation and inducing apoptosis. NSK-01105 appears to be a promising orally active anticancer drug and deserves further investigation.
本研究旨在探讨新型索拉非尼衍生物NSK - 01105在体外和体内模型中的抗肿瘤活性，并探索其潜在机制。通过细胞毒性试验、凋亡分析、流式细胞术分析和蛋白质免疫印迹分析，确定了NSK - 01105对前列腺癌细胞增殖和凋亡的影响。使用两种异种移植肿瘤模型在体内验证NSK - 01105的治疗效果。NSK - 01105表现出广谱抗肿瘤活性，尤其是对前列腺癌细胞。观察到凋亡形态特征，NSK - 01105处理24小时后，凋亡阳性细胞百分比显著增加。此外，通过细胞周期分析确定，NSK - 01105处理后，LNCaP和PC - 3细胞中“亚G1”群体显著增加。每天口服30 mg/kg剂量的NSK - 01105可显著抑制肿瘤生长，在LNCaP模型中的抑制率为63.82%，在PC - 3模型中的抑制率为64.29%。NSK - 01105在10 μmol/L时可下调Raf - 1激酶和表皮生长因子受体的激活。因此，通过蛋白质免疫印迹分析观察到Raf/MEK/ERK和PI3K/Akt/mTOR信号通路的双重抑制。总体而言，我们的结果表明NSK - 01105通过抑制细胞增殖和诱导凋亡在人类前列腺肿瘤治疗中发挥作用。NSK - 01105似乎是一种有前景的口服活性抗癌药物，值得进一步研究。
