The response of mammalian cells to hypoxia is mediated by a family of transcription factors known as HIF (hypoxia-inducible factors). The subunits of HIF, HIF-1α can be degraded rapidly under normoxia. LW6 is a dual inhibitor of HIF-1α and MDH2, which can inhibit activity of HIF-1α with IC50 value of 2.64 ± 0.16 μM (measured by HRE-luciferase activity). LW6 can potently inhibit HIF-1α accumulation by degrading HIF-1α on concentration of 10 μM in HCT116 cells under hypoxia, with no effect on transcription levels during hypoxia. LW6 inhibited the MDH2 activity in a concentration-dependent manner with IC50 value of 6.3 μM, without affecting the MDH2 expression. This HIF-1α inhibitory activity of LW6 may due to the interaction and suppression of MDH2 (malate dehydrogenase 2, a 36 kDa mitochondrial enzyme that catalyzes the malate/NAD+ conversion to oxaloacetate/ NADH during the TCA cycle and functions as a respiratory substrate in the mitochondrial ETC) by LW6[1]. The activity of LW6 against HIF-1α may also due to it promotes proteasomal degradation of HIF-1α via upregulation of VHL. Treatment with LW6 for 13 days, 20 mg/kg, QD, i.p., significantly inhibited HCT116 tumor growth up to 53.6% in a xenograft tumor model compared with the control group[2].
作用机制
The action of LW6 against HIF-1α may due to it can promote proteasomal degradation of HIF-1α via upregulation of VHL, as well as inhibit and bind to MDH2[1][2].
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