Potentiation of naphthoxyloside cytotoxicity on human tumor cells by difluoromethylornithine and spermine-NONOate.
Here we demonstrate a synergistic and tumor selective cytotoxic effect by combined treatment with naphthoxylosides, polyamine synthesis inhibitor, and polyamine based nitric oxide (NO) donor, using in vitro human tumor models. We have earlier reported that heparan sulfate priming naphthoxyloside, 2-(6-hydroxynaphthyl)-O-beta-D-xylopyranoside, which inhibits growth of human tumor cells in vitro and in vivo models, undergoes NO dependent cleavage and accumulates in the nuclei of tumor cells. Polyamine depletion using alpha-difluoromethylornithine (DFMO) increases both the number of NO sensitive sites in heparan sulfate and uptake of the polyamine based NO donor, spermineNONOate, thereby enhancing formation of growth-inhibitory NO induced heparan sulfate products with specific cytotoxic effect on tumor cells. We also show that peracetylation of xylosides doubles the antiproliferative effect towards human cancer cells by making these compounds more permeable to the cells.
Cheng
Fang
F
Department of Experimental Medical Sciences, Biomedical Centre A13, Lund University, SE-221 84 Lund, Sweden.
Johnsson
Richard
R
Nilsson
Jakob
J
Fransson
Lars-Ake
LA
Ellervik
Ulf
U
Mani
Katrin
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology*; D006027:Glycosides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D006027:Glycosides; D009284:Naphthols; D011073:Polyamines; C010807:xylosides; C091861:spermine nitric oxide complex; D013096:Spermine; D000518:Eflornithine