Heparin has been reported as not only an anticoagulant drug but also as a tumoral angiogenesis inhibitor by blocking tumor growth factors including VEGF, bFGF. Low molecular weight heparin conjugated with 4 pairs of deoxycholic acid (LHbisD4) was newly synthesized to enhance the oral absorption and efficacy. As the tumoral lymphangiogenesis is being considered to play the most important role in tumor metastasis, the purpose of this study is to evaluate whether LHbisD4 could suppress the tumoral lymphangiogenesis as well as the incidence of metastasis. To evaluate the inhibition effect of LHbisD4 on VEGF-C induced lymphangiogenesis, several in vitro experiments using human dermal lymphatic endothelial cell(HDLEC) was carried out. The inhibition effect of LHbisD4 on VEGF-C induced VEGFR-3 phosphorylation was evaluated by western blot. Proliferation assay, tubular formation assay, spheroid based sprouting assay were also done to evaluate the efficacy of LHbisD4 on suppressing lymphagiogenesis using HDLEC. For in vivo test, orthotopic breast cancer metastasis model was used and the incidence of metastasis to distant organs was evaluated. We found that VEGF-C induced phosphorylation of VEGFR3 which is the most important signaling cascade to initiate the lymphangiogenesis was highly inhibited in the presence of LHbisD4. Also through other in vitro experiment such as proliferation assay, tubular formation assay, spheroid based sprouting assay, LHbisD4 was proven to be effective enough to suppress VEGF-C induced lymphangiogenesis. In orthotopic model, 10mg/kg/day dose of LHbisD4 was administered orally and we found the incidence of metastasis is highly decreased compared with control group. Especially, weight and volume of the lymph node is highly decreased in case of drug treated group, which means the lymphatic metastasis is significantly suppressed. Through this study, we demonstrate that our novel heparin conjugate could be a good candidate for targeting VEGF-C induced lymphangiogenesis as well as an effective anti-metastatic agent.

Citation Format: Jeong Uk Choi, Youngro Byun. Orally active low molecular weight heparin conjugates as a tumoral lymphangiogenesis inhibitor. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B36.