MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.
Bottom Line: In this study, we further examined the effects of MFTZ-1 on hypoxia-inducible factor-1α (HIF-1α) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis.Mechanistic studies revealed that MFTZ-1 did not affect the degradation of HIF-1α protein or the level of HIF-1α mRNA.The results reveal an important feature that MFTZ-1 can reduce constitutive, HIF-1α-independent VEGF secretion and concurrently antagonize inducible, HIF-1α-dependent VEGF secretion.
Affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.Show MeSH
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Mentions: Previous reports show that compounds capable of reducing HIF-1α accumulation and VEGF secretion simultaneously inhibit angiogenesis directly [15, 32]. Also hypoxia-induced HIF-1α is essential for hypoxia-induced angiogenesis, especially tube formation . To further investigate whether MFTZ-1 has anti-angiogenic effects, we employed a series of standard angiogenesis models. In the HUVEC tube formation assay, MFTZ-1 potently suppressed the cord formation of HUVEC stimulated by hypoxia (Fig. 5A) or serum at normoxia (Fig. 5B) at a concentration as low as 0.04 μM (Fig. 1). In term of endothelial migration, HUVEC chemotactically (20% FBS) moved from the upper side to the lower side of the membrane in the Boyden chamber . MFTZ-1 repressed this process in a concentration-dependent manner (Fig. 5C). An ex vivo model further demonstrated that MFTZ-1 prominently prevented new microvessel outgrowth arising from rat aortic ring (Fig. 5D). All the experiments were manipulated with MFTZ-1 at its sub-cytotoxic concentration regimens (0.008 μM to 1 μM), the concentration of which is 10-fold lower than required for its targeting Top2 .
Affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.