TY - JOUR
T1 - Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase
AU - Chumanevich, Alexander A.
AU - Poudyal, Deepak
AU - Cui, Xiangli
AU - Davis, Tia
AU - Wood, Patricia A.
AU - Smith, Charles D.
AU - Hofseth, Lorne J.
N1 - Funding Information:
We thank the Statistical Core (Dr Edsel Pena, Director) and Mouse Core (Dr Marj Pena, Director) at University of South Carolina. Thanks also to Imaging/ Histology Core supported by the Center for Colon Cancer Research and the Lipidomics Core at Medical University of South Carolina. Thanks also to Imaging/Histology Core supported by the Center for Colon Cancer Research, National Center for Research Resources, National Institutes of Health and the Lipidomics Core at Medical University of South Carolina.
PY - 2010/8/5
Y1 - 2010/8/5
N2 - 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 antiinflammatory 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.
AB - 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 antiinflammatory 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.
UR - http://www.scopus.com/inward/record.url?scp=77957770455&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957770455&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgq158
DO - 10.1093/carcin/bgq158
M3 - Article
C2 - 20688834
AN - SCOPUS:77957770455
VL - 31
SP - 1787
EP - 1793
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 10
ER -