Neoglycans, carbodiimide-modified glycosaminoglycans: a new class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis.
The soluble form of the syndecan-1 heparan sulfate proteoglycan acts as a tumor suppressor molecule that inhibits growth and induces apoptosis of some cancer cell lines in vitro. Analogs of syndecan-1 were produced by carbodiimide (EDAC) conjugation of glycosaminoglycan (GAG) chains to a protein scaffold, thereby generating synthetic proteoglycans that were evaluated for anticancer properties. Surprisingly, when analyzing activities of the controls, we discovered that EDAC modified GAG chains inhibit myeloma cell viability even in the absence of protein. Here, we describe the production and the activities of these novel molecules called neoglycans. The GAG chains heparin and chondroitin sulfate (CS) were exposed to EDAC to generate the neoglycans neoheparin and neoCS, respectively. Heparin and CS in the absence of EDAC modification have no effect or a slight growth promoting effect on cancer and normal cell lines. However, neoheparin and neoCS substantially reduce cell viability by induction of apoptosis of myeloma and breast cancer cells in vitro. NeoCS when injected directly into breast tumors growing in nude mice reduces or abolishes their growth without causing apparent toxicity to the adjacent normal tissue. The neoglycans need not be continuously present in cell cultures because a short pulse exposure is sufficient to reduce cell viability. NeoCS fractions purified by size exclusion chromatography reduce myeloma cell viability, confirming the specificity of neoglycan activity. Collectively, the results of this study demonstrate the anticancer activities of this new class of GAG chain-based molecules and provide the foundation for future development of neoglycans as novel therapeutic agents.
Pumphrey
Carla Y
CY
Arkansas Cancer Research Center, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Theus
Allison M
AM
Li
Shulin
S
Parrish
Rudolph S
RS
Sanderson
Ralph D
RD
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D016466:CHO Cells; D002234:Carbodiimides / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology*; D006493:Heparin / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D011509:Proteoglycans / Q000737:chemistry / Q000494:pharmacology; D053668:Syndecan-1; D053667:Syndecans; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002234:Carbodiimides; D006025:Glycosaminoglycans; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; C074139:1-ethyl-3-(3-dimethylaminoethyl)carbodiimide; D006493:Heparin; D002809:Chondroitin Sulfates