title: Targeting colorectal cancer cells by a novel sphingosine kinase 1 inhibitor PF-543.
abstract: In this study, we showed that PF-543, a novel sphingosine kinase 1 (SphK1) inhibitor, exerted potent anti-proliferative and cytotoxic effects against a panel of established (HCT-116, HT-29 and DLD-1) and primary human colorectal cancer (CRC) cells. Its sensitivity was negatively associated with SphK1 expression level in the CRC cells. Surprisingly, PF-543 mainly induced programmed necrosis, but not apoptosis, in the CRC cells. CRC cell necrotic death was detected by lactate dehydrogenase (LDH) release, mitochondrial membrane potential (MMP) collapse and mitochondrial P53-cyclophilin-D (Cyp-D) complexation. Correspondingly, the necrosis inhibitor necrostatin-1 largely attenuated PF-543-induced cytotoxicity against CRC cells. Meanwhile, the Cyp-D inhibitors (sanglifehrin A and cyclosporin A), or shRNA-mediated knockdown of Cyp-D, remarkably alleviated PF-543-induced CRC cell necrotic death. Reversely, over-expression of wild-type Cyp-D in HCT-116 cells significantly increased PF-543's sensitivity. In vivo, PF-543 intravenous injection significantly suppressed HCT-116 xenograft growth in severe combined immunodeficient (SCID) mice, whiling remarkably improving the mice survival. The in vivo activity by PF-543 was largely attenuated when combined with the Cyp-D inhibitor cyclosporin A. Collectively, our results demonstrate that PF-543 exerts potent anti-CRC activity in vitro and in vivo. Mitochondrial programmed necrosis pathway is likely the key mechanism responsible for PF-543's actions in CRC cells.
authors.affiliation: Department of Anal-colorectal Surgery, HangZhou First People's Hospital, HangZhou, China.
authors.forename: TongFa
authors.initials: T
authors.lastname: Ju
authors.affiliation: Hematological Department, HangZhou First People's Hospital, HangZhou, China.
authors.forename: DaQuan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Anal-colorectal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. Electronic address: fangzhengyu158@sina.com.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000432:Methanol; D051379:Mice; D016513:Mice, SCID; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage*; D013450:Sulfones / Q000008:administration & dosage*; D015996:Survival Rate; D016896:Treatment Outcome; D000099157:Sphingosine Kinase
chemical_list: D000432:Methanol; D017853:Phosphotransferases (Alcohol Group Acceptor); D011759:Pyrrolidines; D013450:Sulfones; D000099157:Sphingosine Kinase; C573330:PF-543
keywords: Colorectal cancer; PF-543; Programmed necrosis; Sphingosine kinase 1