Tumor attenuation by combined heparan sulfate and polyamine depletion.

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Abstract

Cells depend on polyamines for growth and their depletion represents a strategy for the treatment of cancer. Polyamines assemble de novo through a pathway sensitive to the inhibitor, alpha-difluoromethylornithine (DFMO). However, the presence of cell-surface heparan sulfate proteoglycans may provide a salvage pathway for uptake of circulating polyamines, thereby sparing cells from the cytostatic effect of DFMO. Here we show that genetic or pharmacologic manipulation of proteoglycan synthesis in the presence of DFMO inhibits cell proliferation in vitro and in vivo. In cell culture, mutant cells lacking heparan sulfate were more sensitive to the growth inhibitory effects of DFMO than wild-type cells or mutant cells transfected with the cDNA for the missing biosynthetic enzyme. Moreover, extracellular polyamines did not restore growth of mutant cells, but completely reversed the inhibitory effect of DFMO in wild-type cells. In a mouse model of experimental metastasis, DFMO provided in the water supply also dramatically diminished seeding and growth of tumor foci in the lungs by heparan sulfate-deficient mutant cells compared with the controls. Wild-type cells also formed tumors less efficiently in mice fed both DFMO and a xylose-based inhibitor of heparan sulfate proteoglycan assembly. The effect seemed to be specific for heparan sulfate, because a different xyloside known to affect only chondroitin sulfate did not inhibit tumor growth. Hence, combined inhibition of heparan sulfate assembly and polyamine synthesis may represent an additional strategy for cancer therapy.

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Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Neoplasm Metastasis, Models Genetic, Models Biological, Mice SCID, Mice, Heparitin Sulfate : pharmacology, Hamsters, Glucuronosyltransferase : biosynthesis, Female, Enzyme Inhibitors : pharmacology, Eflornithine : pharmacology, Dose-Response Relationship Drug, DNA Complementary : metabolism, CHO Cells, Animal, Antineoplastic Agents : pharmacology, Neoplasm Transplantation, Polyamines : metabolism, Proteoglycans : metabolism, Spermine : pharmacology, Support Non-U.S. Gov't, Support U.S. Gov't P.H.S., Time Factors
Original languageEnglish
Pages (from-to)371-376
JournalProceedings of the National Academy of Sciences
Volume99
Issue number1
Publication statusPublished - 2002
Publication categoryResearch
Peer-reviewedYes