3-(4-chlorophenyl)-adamantane-1-carboxylic-acid-(pyridin-4-ylmethyl)amide and Colorectal-Neoplasms

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.

Topics: Adamantane; Animals; Antineoplastic Agents; Cell Proliferation; Cisplatin; Colorectal Neoplasms; Female; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Male; MAP Kinase Signaling System; Mice, Nude; Middle Aged; Phosphotransferases (Alcohol Group Acceptor); Pyridines; Xenograft Model Antitumor Assays