title: Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells.
abstract: Recent published studies suggest that increasing levels of ceramides enhance the chemo-sensitivity of curcumin. Using in vitro approaches, we analyzed the impact of sphingosine kinase-1 (SphK-1) inhibition on ceramide production, and evaluated SphK1 inhibitor II (SKI-II) as a potential curcumin chemo-sensitizer in ovarian cancer cells. We found that SphK1 is overexpressed in ovarian cancer patients' tumor tissues and in cultured ovarian cancer cell lines. Inhibition of SphK1 by SKI-II or by RNA interference (RNAi) knockdown dramatically enhanced curcumin-induced apoptosis and growth inhibition in ovarian cancer cells. SKI-II facilitated curcumin-induced ceramide production, p38 activation and Akt inhibition. Inhibition of p38 by the pharmacological inhibitor (SB 203580), a dominant-negative expression vector, or by RNAi diminished curcumin and SKI-II co-administration-induced ovarian cancer cell apoptosis. In addition, restoring Akt activation introducing a constitutively active Akt, or inhibiting ceramide production by fumonisin B1 also inhibited the curcumin plus SKI-II co-administration-induced in vitro anti-ovarian cancer effect, suggesting that ceramide accumulation, p38 activation and Akt inhibition are downstream effectors. Our findings suggest that low, well-tolerated doses of SKI-II may offer significant improvement to the clinical curcumin treatment of ovarian cancer.
authors.affiliation: Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yan-li
authors.initials: YL
authors.lastname: Yang
authors.forename: Chao
authors.initials: C
authors.lastname: Ji
authors.forename: Lei
authors.initials: L
authors.lastname: Cheng
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Chun-cheng
authors.initials: CC
authors.lastname: Lu
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Zhi-gang
authors.initials: ZG
authors.lastname: Bi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002518:Ceramides / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006131:Growth Inhibitors; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014162:Transfection; D000099157:Sphingosine Kinase
chemical_list: D051017:Apoptosis Regulatory Proteins; D002518:Ceramides; D003474:Curcumin; D006131:Growth Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D000099157:Sphingosine Kinase