Abstract
Increasing evidence indicates that Nrf-2, named the nuclear factor-erythroid 2-related factor, may perform anticancer function. In this study, a series of novel substituted phenyl- (3-methyl-1H-indol-2-yl)-prop-2-en-1-one (indolyl-chalcone) derivatives were synthesized and their effects on Nrf-2 activity were observed. We found that compounds 3a-3d and 6c elevated Nrf-2 activity. Then we evaluated their anticancer activities in vitro and in vivo by utilizing human lung cancer cell line A549. The in vitro results showed that among the compounds, 3d performed effectively anti-growth activity by inducing A549 lung cancer cell apoptosis and activating Nrf-2/HO-1 (heme oxygenase-1) pathway. In vivo, we proved that compound 3d inhibited the tumor growth effectively through inducing cell apoptosis without affecting CAM normal angiogenesis. These data suggest that our discovery of a novel Nrf-2 activator compound 3d would provide a new point of human lung cancer treatment.
Highlights
Lung cancer is a considerable worldwide public health concern
As Nrf-2 activators have shown much incredible potential in disease prevention[33], especially in cancer treatment, we firstly analyzed endogenous Nrf-2 activity in HeLa cells which were transfected with luciferase-based Nrf-2 reporter plasmid after treatment with a series of novel substituted phenyl-(3-methyl-1H-indol-2-yl)-prop-2-en-1-one, indolyl-chalcone derivatives (3a -3d, 6a-6e)
In order to find out how these compounds influenced tumor cells growth as Nrf-2 activators, we selected A549 lung cancer cells for the following research
Summary
Lung cancer is a considerable worldwide public health concern. Comparing with the survival rates of other cancers, 5-years survival rate of lung cancer is lower[1]. Many reports have displayed that minor structural transformation of chalcones could induce considerable difference in the effect of anticancer, anti-inflammatory or autoimmune diseases[6, 7]. A novel quinazolinone chalcone derivative (QC) has been reported to inhibit PI3K/Akt/mTOR signaling pathway and trigger human HCT-116 cells apoptosis[13]. Chalcones as immunomodulatory drugs show different effects on various immune cells, including triggering apoptosis in dendritic cells[17], inhibiting superoxide anion production by weakening the activity of PKC in PMA-induced rat neutrophils[18], performing anti-inflammatory potential in monocytes and macrophages[19], suppressing rabbit platelets aggregation caused by arachidonic acid or collagen[20, 21], inhibiting the generation of functional cytotoxic T cells from mouse spleen and so on[22]. Indole derivatives have attracted many researchers’ attention and a lot of indole derivatives have been synthesized or extracted from natural resources[28]
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