Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase.
Sphingolipid metabolism is driven by inflammatory cytokines. These cascade of events include the activation of sphingosine kinase (SK), and subsequent production of the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). Overall, S1P is one of the crucial components in inflammation, making SK an excellent target for the development of new anti-inflammatory drugs. We have recently shown that SK inhibitors suppress colitis and hypothesize here that the novel SK inhibitor, ABC294640, prevents the development of colon cancer. In an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model, there was a dose-dependent decrease in tumor incidence with SK inhibitor treatment. The tumor incidence (number of animals with tumors per group) in the vehicle, ABC294640 (20 mg/kg) and ABC294640 (50 mg/kg) groups were 80, 40 and 30%, respectively. Tumor multiplicity (number of tumors per animal) also decreased from 2.1 ± 0.23 tumors per animal in the AOM + DSS + vehicle group to 1.2 ± 0 tumors per animal in the AOM + DSS + ABC294640 (20 mg/kg) and to 0.8 ± 0.4 tumors per animal in the AOM + DSS + ABC294640 (50 mg/kg) group. Importantly, with ABC294640, there were no observed toxic side effects. To explore mechanisms, we isolated cells from the colon (CD45-, representing primarily colon epithelial cells) and (CD45+, representing primarily colon inflammatory cells) then measured known targets of SK that control cell survival. Results are consistent with the hypothesis that the inhibition of SK activity by our novel SK inhibitor modulates key pathways involved in cell survival and may be a viable treatment strategy for the chemoprevention colitis-driven colon cancer.
Chumanevich
Alexander A
AA
Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina and Medical University of South Carolina, Columbia, SC 29208, USA.
Poudyal
Deepak
D
Cui
Xiangli
X
Davis
Tia
T
Wood
Patricia A
PA
Smith
Charles D
CD
Hofseth
Lorne J
LJ
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D003092:Colitis / Q000150:complications / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011725:Pyridines / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D000099157:Sphingosine Kinase
D000218:Adamantane; D001397:Azoxymethane; D016264:Dextran Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide