Folate receptor (FR) overexpression in a wide range of solid
tumors provides an opportunity to develop novel, targeted
cancer therapeutics. In this study, we investigated whether prebinding the chemotherapeutic
methotrexate (MTX) to
folate-
binding protein (FBP), the soluble form of FR, would enable the
protein to serve as a targeted therapeutic vector, enhancing uptake into
tumor cells and improving therapeutic efficacy. In an in vivo study, using an FR-overexpressing KB xenograft model in SCID mice, modest improvement in inhibiting
tumor growth was observed for the MTX/FBP mixtures as compared to saline control and free MTX. Surprisingly, FBP alone inhibited
tumor growth compared to saline control, free MTX, and FBP/MTX. In order to better understand this effect, we investigated the cytotoxicity of micromolar concentrations of FBP in vitro using the KB, HeLa, and A549
cancer cell lines. Our results revealed concentration-dependent apoptosis (24 h; 10-50 μM) in all three cell lines accompanied by a time- and concentration-dependent reduction (6, 12, and 24 h; 10-50 μM) in metabolic activity and compromised cell plasma membrane integrity. This study demonstrates an apoptosis pathway for cytotoxicity of FBP, an endogenous
serum protein, in
cancer cell lines with widely varying levels of FR expression. Furthermore, in vivo
tumor growth suppression for xenograft KB
tumors in SCID mice was observed. These studies suggest novel strategies for the elimination of
cancer cells employing endogenous, serum
transport proteins.