MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.

ABSTRACT: The macrolide compound MFTZ-1 has been identified as a novel topoisomerase II (Top2) inhibitor with potent in vitro and in vivo anti-tumour activities. 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. MFTZ-1 reduced HIF-1α accumulation driven by hypoxia or growth factors in human cancer cells. Mechanistic studies revealed that MFTZ-1 did not affect the degradation of HIF-1α protein or the level of HIF-1α mRNA. By contrast, MFTZ-1 apparently inhibited constitutive and inducible activation of both phosphatidylinositol-3-kinase (PI3K)-Akt and p42/p44 mitogen-activated protein kinase (MAPK) pathways. Further studies revealed that MFTZ-1 abrogated the HIF-1α-driven

SUBMITTER: Dai M 

PROVIDER: S-EPMC3822569 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature