2,2′-Dithiobis(N-ethyl-spermine-5-carboxamide) Is a High Affinity, Membrane-impermeant Antagonist of the Mammalian Polyamine Transport System

Huber, Maria; Pelletier, Joële G.; Torossian, Krikor; Dionne, P.; Gamache, Isabelle; Charest-Gaudreault, René; Audette, Marie; Poulin, Richard

doi:10.1074/jbc.271.44.27556

Cited by 29 publications

(29 citation statements)

References 42 publications

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“…Notable examples of potent polyamine transport inhibitors include the work by Poulin55;56 and Cullis 5758 Two groups have summarized much of this literature data by use of CoMFA and QSAR methods 59…”

Section: Discussionmentioning

confidence: 99%

Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

et al. 2009

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Cancer cells can overcome the ability of polyamine biosynthesis inhibitors from completely depleting their internal polyamines by the importation polyamines from external sources. We have developed a group of lipophilic polyamine analogs that potently inhibit the cellular polyamine uptake system and greatly increase the effectiveness of polyamine depletion when used in combination with DFMO, a well-studied polyamine biosynthesis inhibitor. By the attachment of an length-optimized C 16 lipophilic substituent to the epsilon-nitrogen atom of our earlier lead compound, D-Lys-Spm (5), we have produced an analog, D-Lys(C 16 acyl)-Spm (11) with several orders of magnitude more potent cell growth inhibition on a variety of cultured cancer cell types including breast (MDA-MB-231), prostate (PC-3), melanoma (A375) and ovarian (SK-OV-3), among others. We discuss these results in the context of a possible membrane-catalyzed interaction with the extracellular polyamine transport apparatus. The resulting novel two-drug combination therapy targeting cellular polyamine metabolism has shown exceptional efficacy against cutaneous squamous cell carcinomas (SCC) in a transgenic ornithine decarboxylase (ODC) mouse model of skin cancer. A majority (88%) of large, aggressive SCCs exhibited complete or near-complete remission to this combination therapy, while responses to each agent alone were poor. The availability of a potent polyamine transport inhibitor allows, for the first time, for a real test of the hypothesis that starving cells of polyamines will lead to objective clinical response.

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Section: Discussionmentioning

confidence: 99%

Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

et al. 2009

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“…Thiols were derivatized with monobromobimane and separated by high‐performance liquid chromatography (HPLC) as described previously (Mukhopadhyay et al ., 1996a). Total intracellular polyamines were extracted from parasites in their exponential phase of growth with 10% (w/v) trichloroacetic acid at 4°C and, after centrifugation for 5 min at 4°C, supernatants were filtered and analysed for polyamine contents by ion‐pair reverse‐phase HPLC, using post‐column derivatization with o ‐phthaldialdehyde and fluorescence detection as described previously (Lessard et al ., 1995; Huber et al ., 1996).…”

Section: Methodsmentioning

confidence: 99%

Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite‐resistant Leishmania

Haimeur

Guimond

Pilote

et al. 1999

Molecular Microbiology

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127

106

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SummaryThe levels of trypanothione, a glutathione±spermidine conjugate, are increased in the protozoan parasite Leishmania selected for resistance to the heavy metal arsenite. The levels of putrescine and spermidine were increased in resistant mutants. This increase is mediated by overexpression of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Gene overexpression is generally mediated by gene ampli®cation in Leishmania but, here, the mRNA and the enzymatic activity of ODC are increased without gene ampli®cation. This RNA overexpression is stable when cells are grown in the absence of the drug and does not result from gene rearrangements or from an increased rate of RNA synthesis. Transient transfections suggest that mutations in the revertant cells contribute to these elevated levels of RNA. Stable transfection of the ODC gene increases the level of trypanothione, which can contribute to arsenite resistance. In addition to ODC overexpression, the gene for the ABC transporter PGPA is ampli®ed in the mutants. The co-transfection of the ODC and PGPA genes confers resistance in a synergistic fashion in partial revertants, also suggesting that PGPA recognizes metals conjugated to trypanothione.

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“…Attempts have been made to specifically inhibit polyamine uptake using polyamine analogues with high affinity for the polyamine carrier without being used as substrates [9,36]. An alternative strategy to inhibit polyamine transport would be to design compounds with structural resemblance to a putative transporter.…”

Section: Discussionmentioning

confidence: 99%

Proteoglycan involvement in polyamine uptake

Belting

Persson

Fransson

1999

Biochemical Journal

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We have evaluated the possible role of proteoglycans in the uptake of spermine by human lung fibroblasts. Exogenous glycosaminoglycans behaved as competitive inhibitors of spermine uptake, the most efficient being heparan sulphate (K i l 0.16p0.04 µM). Treatment of fibroblasts with either heparan sulphate lyase, p-nitrophenyl-O-β--xylopyranoside or chlorate reduced spermine uptake considerably, whereas chondroitin sulphate lyase had a limited effect. Inhibition of polyamine biosynthesis with α-difluoromethylornithine resulted in an increase of cell-associated heparan sulphate proteoglycans exhibiting higher affinity for spermine. The data indicate a specific role for heparan sulphate proteoglycans in the uptake of spermine by fibroblasts. Spermine uptake by pgsD-677, a mutant Chinese hamster ovary cell defective in heparan sulphate biosynthesis, was only moderately reduced (20 %) compared with wild-type

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2,2′-Dithiobis(N-ethyl-spermine-5-carboxamide) Is a High Affinity, Membrane-impermeant Antagonist of the Mammalian Polyamine Transport System

Cited by 29 publications

References 42 publications

Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite‐resistant Leishmania

Proteoglycan involvement in polyamine uptake

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