Increased in Vitro Cytotoxicity of TNF-? Analog LK-805 Is Based on the Interaction with Cell Surface Heparan Sulfate Proteoglycan
Our tumor necrosis factor-alpha (TNF-?) analog LK-805 (E107K) exhibited twofold higher specific cytotoxicity on the mouse fibroblast L-929 cell line than its native counterpart. In addition, significantly lowered systemic toxicity was observed in tumor-bearing mouse models treated with this analog. Due to a charge reversal and clustering of three lysines in the exposed tip region of LK-805, we assumed that additional ionic interactions between the positively charged TNF analog and the negatively charged components of the cell surface were created, which might contribute to improved properties of LK-805. To prove this hypothesis, we designed truncated forms of TNF-? and analog LK-805 and performed three independent sets of experiments
cytotoxicity heparan sulfate proteoglycans tumor necrosis factor-alpha tnf analog cell line l-929 heparin sepharose cancer therapy