Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):456-62. doi: 10.1016/j.ijrobp.2013.01.025. Epub 2013 Mar 6.
Hepatocellular carcinoma (HCC) is one of the most common and lethal human malignancies. Lack of efficient therapy for advanced HCC is a pressing problem worldwide. This study aimed to determine the efficacy and mechanism of combined sorafenib and radiation therapy treatment for HCC.
HCC cell lines (PLC5, Huh-7, Sk-Hep1, and Hep3B) were treated with sorafenib, radiation, or both, and apoptosis and signal transduction were analyzed.
All 4 HCC cell lines showed resistance to radiation-induced apoptosis; however, this resistance could be reversed in the presence of sorafenib. Inhibition of phospho-STAT3 was found in cells treated with sorafenib or sorafenib plus radiation and subsequently reduced the expression levels of STAT3-related proteins, Mcl-1, cyclin D1, and survivin. Silencing STAT3 by RNA interference overcame apoptotic resistance to radiation in HCC cells, and the ectopic expression of STAT3 in HCC cells abolished the radiosensitizing effect of sorafenib. Moreover, sorafenib plus radiation significantly suppressed PLC5 xenograft tumor growth.
These results indicate that sorafenib sensitizes resistant HCC cells to radiation-induced apoptosis via downregulating phosphorylation of STAT3 in vitro and in vivo.
肝细胞癌（HCC）是最常见和最致命的人类恶性肿瘤之一。缺乏有效的晚期 HCC 治疗方法是全世界面临的紧迫问题。本研究旨在确定索拉非尼联合放射治疗 HCC 的疗效和机制。
用索拉非尼、放疗或两者联合处理 HCC 细胞系（PLC5、Huh-7、Sk-Hep1 和 Hep3B），并分析细胞凋亡和信号转导。
所有 4 种 HCC 细胞系均对放射诱导的细胞凋亡表现出耐药性；然而，索拉非尼的存在可以逆转这种耐药性。在索拉非尼或索拉非尼联合放疗处理的细胞中发现磷酸化-STAT3 被抑制，随后降低了 STAT3 相关蛋白、Mcl-1、细胞周期蛋白 D1 和生存素的表达水平。通过 RNA 干扰沉默 STAT3 可克服 HCC 细胞对放射的凋亡抵抗，并且 HCC 细胞中 STAT3 的异位表达可消除索拉非尼的放射增敏作用。此外，索拉非尼联合放疗显著抑制了 PLC5 异种移植肿瘤的生长。
这些结果表明，索拉非尼通过下调体外和体内 STAT3 的磷酸化，使耐药 HCC 细胞对放射诱导的细胞凋亡敏感。
