Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
Cai Xun, Min-Bin Chen, Li Qi, Zhang Tie-Ning, Xue Peng, Li Ning, Chen Zhi-Xiao, Wang Li-Wei
文献索引:J. Exp. Clin. Cancer Res 34 , 94, (2015)
全文:HTML全文
摘要
Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.
相关化合物
相关文献:
2014-09-30
[Oncotarget 5(18) , 8107-22, (2014)]
2014-10-15
[Eur. J. Pharm. Sci. 63 , 14-21, (2014)]
2015-01-07
[World J. Gastroenterol. 21(1) , 164-76, (2015)]
[Iran. J. Pharm. Res. 14(2) , 395-405, (2015)]
2015-08-01
[Cancer Sci. 106 , 1000-7, (2015)]