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: Our previous study shows that MFTZ-1 has an averaged IC50 of 0.99 μM for the exposure duration of 72 hrs in MDA-MB-231 cells . In this study, we found MFTZ-1 to be non- to sub-cytotoxic (growth inhibition <20%vs control) to MDA-MB-231 cells in the range of 0.008 μM to 1 μM for 6 hrs and 16 hrs (data not shown). To examine whether MFTZ-1 decreases the level of cellular HIF-α protein, we used these concentrations of the compound to treat human cancer cells under various conditions. When human breast cancer MDA-MB-231 cells were exposed to hypoxia (1% O2), the level of HIF-1α protein first rose, peaked at the time-point of 6–16 hrs, and then came down (Fig. 1A). Treatment of the cells with MFTZ-1 in hypoxia led to concentration-dependent reduction of cellular HIF-1α protein (Fig. 1B). Similarly, MFTZ-1 also abrogated the accumulation of HIF-1α protein driven by the growth factors EGF (Fig. 1C), which are known to stimulate the expression of HIF-1α protein [5, 6, 25]. Moreover, the levels of HIF-1α protein at hypoxic conditions were diminished by MFTZ-1 in a panel of tumour cell lines with different tissues of origin including breast cancer MDA-MB-468, colon cancer HCT-116, lung cancer A549, melanoma A375 and cervical cancer HeLa cell lines (Fig. 1D). In addition, MFTZ-1 was not revealed to inhibit HIF-2α in SKBr3 and 786-O cells (Fig. S4; HIF-2α was undetectable in MDA-MB-231 cells under the same condition). All these substantiate a universal reduction of HIF-1α protein induced by MFTZ-1 under the complicated conditions including tumour cells with different tissues of origin, normoxia, hypoxia, and stimulation with growth factors, most of which occur in the human body.
Affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.