Poster Presenter

Anti-Tumor Activity And Mechanisms of a Novel Vascular Disrupting Agent (Z)-3,4',5-Trimethoxylstilbene-3'-O-Phosphate Disodium
Yu-Chen Cai, Yong Zou, Yan-Li Ye, Hong-Yi Sun, Quan-Guan Su, Zhi-Xin Wang, Zhao-Lei Zeng, Li-Jian Xian
China

Vascular disrupting agents (VDAs) present a new sort of anti-cancer drugs in the recent years. Structure modification of active parent compound is an effective approach to develop new agents with more activity and less adverse reaction. In our study, 6 synthesized diphenyl ethylene compounds were screened for their cytotoxic activity against human tumor cells and the mechanisms were studied. MTT assay was used to test the anti-proliferation activity; Polymerization of tubulin was detected by tubulin assembly assay; The cellular microtubule network was observed by immunocytochemical study; Cell-cycle distribution was detected by flow cytometry; Wright-Giemsa staining was performed to demonstrate the morphological features of cells in mitotic phase; A model of nude mice with xenografted colon cancer was used to demonstrate the in vivo anti-tumor activity and the micro vessel density (MVD) was determined by immunohistochemistry; The expression levels of protein and mRNA were detected by Western blot and RT-PCR respectively. Among 6 new synthesized compound, (Z)-3,4',5-trimethoxylstilbene-3'-O-phosphate disodium (M410) showed potent cytotoxic activity toward proliferating tumor cells and exhibited the similar cytotoxicity against the multi-drug resistance (MDR) tumor cells. M410 inhibited the bovine brain tubulin polymerization in a similar way with colchicines. In proliferating human umbilical vein endothelial cells (HUVECs), M410 of 20nM induced cellular tubulin depolymerization within 4 hours and lead to M phase arrest. Systemic administration of M410 at nontoxic doses in nude mice resulted in inhibition of tumor growth of human colon cancer LoVo xenografts. The tumor vessel density decreased, as determined by immunohistochemical staining for CD31 after M410 treatment. M410 down-regulated the hypoxia-inducible factor-1 alpha (HIF-1α) expression, reduced the nuclear HIF-1α, and then down-regulated the vascular endothelial cell growth factor (VEGF) mRNA. M410 inhibited tubulin polymerization and inhibited tumor growth of human xenografts in vivo. M410 is a potent microtubule inhibitor combined cytotoxic, angiogenesis inhibiting and vascular targeting.