Kim Hee Man, Kim Sun A, Park Soo Been, Cho Jae Hee, Song Si Young
a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.
b Division of Gastroenterology and Hepatology, Department of Internal Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.
Scand J Gastroenterol. 2017 May;52(5):577-584. doi: 10.1080/00365521.2017.1278786. Epub 2017 Jan 22.
Sorafenib is a multi-kinase inhibitor used in the treatment of various cancers. This study investigated the inhibitory effect of sorafenib on xenograft models of gastric cancer cells and 5-fluorouracil (5-FU)-resistant cells.
The half-maximal inhibitory concentration (IC) of sorafenib in NCI-N87 cells was determined. Xenograft models were established using BALB/c nude mice and were divided into four groups treated with vehicle, sorafenib (20 mg kg day), 5-FU (50 mg kg week), or a combination of sorafenib (20 mg kg day) plus 5-FU (50 mg kg week). 5-FU-resistant NCI-N87 cells were established by repeated exposure to 5-FU.
Sorafenib inhibited NCI-N87 cell growth in a concentration-dependent manner with a mean IC of 16.345 ± 5.391 μM. Phosphorylation levels of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase in these cells decreased in a dose-dependent manner after exposure to sorafenib. Sorafenib induced the activation of caspase-3, and its combination with 5-FU more effectively inhibited the growth of xenograft tumors than either sorafenib or 5-FU alone (p < 0.05). Sorafenib markedly inhibited 5-FU-resistant NCI-N87 cell growth as well as sphere formation in both parental and 5-FU-resistant NCI-N87 cells.
The sorafenib and 5-FU combination exhibited enhanced antitumor effects in a gastric cancer xenograft model and inhibited 5-FU-resistant cell proliferation and sphere formation. These findings suggest that sorafenib is useful in overcoming gastric cancer resistance to conventional chemotherapy.
索拉非尼是一种用于治疗多种癌症的多激酶抑制剂。本研究调查了索拉非尼对胃癌细胞和5-氟尿嘧啶（5-FU）耐药细胞异种移植模型的抑制作用。
测定索拉非尼在NCI-N87细胞中的半数最大抑制浓度（IC）。使用BALB/c裸鼠建立异种移植模型，并将其分为四组，分别用赋形剂、索拉非尼（20mg/kg/天）、5-FU（50mg/kg/周）或索拉非尼（20mg/kg/天）加5-FU（50mg/kg/周）联合治疗。通过反复暴露于5-FU建立5-FU耐药的NCI-N87细胞。
索拉非尼以浓度依赖的方式抑制NCI-N87细胞生长，平均IC为16.345±5.391μM。这些细胞中丝裂原活化蛋白激酶激酶和细胞外信号调节激酶的磷酸化水平在暴露于索拉非尼后呈剂量依赖性降低。索拉非尼诱导半胱天冬酶-3的激活，其与5-FU联合使用比单独使用索拉非尼或5-FU更有效地抑制异种移植肿瘤的生长（p<0.05）。索拉非尼显著抑制5-FU耐药的NCI-N87细胞生长以及亲本和5-FU耐药的NCI-N87细胞中的球状体形成。
索拉非尼与5-FU联合在胃癌异种移植模型中表现出增强的抗肿瘤作用，并抑制5-FU耐药细胞的增殖和球状体形成。这些发现表明索拉非尼有助于克服胃癌对传统化疗的耐药性。
