Galectins belong to the family of mammalian lectins sharing an evolutionary conserved sequence in their carbohydrate recognition binding (CRD) domains and exhibit a characteristic affinity for beta-galactoside-sugars. Based on their structure and CRD, galectins have been categorized into three different categories: 1) Prototype (Gal-1, 2, 5, 7, 10, 11, 13, and 14), 2) Chimera type (Gal-3), and 3) Tandem repeat type (Gal-6, 8, 9, and 12). In particular, Galcetin-3 (Gal-3) is associated with growth, differentiation, adhesion, RNA processing, and apoptosis

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Apoptosis
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2005
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10
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267
–75)
. Previous studies show that Gal-3 is expressed on tumor cell surface and mediate the transformation and metastasis of tumor cells in vivo
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Apoptosis
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2005
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10
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267
–75)
. Here, we show that Gal-3 is differentially expressed in multiple myeloma (MM) cell lines and purified patient cells, as determined by both western blotting and polymerase chain reaction (PCR). Importantly, Gal-3 shares structural similarities with the anti-apoptotic protein Bcl-2: both proteins are rich in proline, glycine, and alanine amino acid residues in their NH-2-terminal domains and contain anti-death motif Asp-Trp-Gly-Arg (NWGR) in their C-terminal domains
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Proc Natl Acad Sci USA
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1996
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93
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6737
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. Gal-3, like Bcl-2, is therefore a potential therapeutic target. In this context, modified citrus pectins (MCP) have been reported to bind and inhibit Gal-3-induced human umbilical endothelial cell migration and micro vessel tube formation
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Am J Pathol.
2000
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156
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899
–909)
as well as block tumor growth and metastasis (J Natl Cancer Inst. 2002, 94:1854–62). GCS-100 is a MCP currently under clinical development. Here we show that GCS-100 binds to human recombinant Gal-3. In MM cells, GCS-100 triggers apoptosis and enhances anti-tumor activity of the conventional agent Dexamethasone. We examined whether GCS-100-, Dex- or GCS-100 + Dex-induced MM cell death modulates Gal-3 or Bcl-2 expression. Treatment of MM.1S cells with either GCS-100 or Dex alone does not alter Gal-3 or Bcl-2 expression. However, combined treatment of MM cells with sub-toxic concentrations of GCS-100 and Dex markedly attenuates Gal-3 expression, without any changes in Bcl-2 levels, suggesting that alterations in Gal-3 are specific. Previous studies showed that Gal-3 inhibits mitochondrial pro-apoptotic protein cytochrome-c (cyto-c), and our results show that GCS-100 + Dex triggers the release of cyto-c from mitochondria to cytosol. Together, these data suggest that the combination of GCS-100 + Dex overcomes the inhibitory effect of Gal-3 on cyto-c, thereby inducing apoptosis. Since Gal-3 is widely expressed in MM cells, its inhibition may augment the anti-tumor activity of therapeutic regimens.

Topics:
carbohydrates, combined modality therapy, dexamethasone, galectin 3, glasgow coma scale, multiple myeloma, neoplasms, neoplasm metastasis, polymerase chain reaction, adhesions

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2005, The American Society of Hematology
2005
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