Open AccessSL4, a chalcone‐based compound, induces apoptosis in human cancer cells by activation of the ROS/MAPK signalling pathway
Author(s) -
Wang L.H.,
Li H.H.,
Li M.,
Wang S.,
Jiang X.R.,
Li Y.,
Ping G.F.,
Cao Q.,
Liu X.,
Fang W.H.,
Chen G.L.,
Yang J.Y.,
Wu C.F.
Publication year - 2015
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12226
Subject(s) - apoptosis , p38 mitogen activated protein kinases , xiap , microbiology and biotechnology , mapk/erk pathway , survivin , kinase , reactive oxygen species , biology , cancer cell , chemistry , programmed cell death , biochemistry , cancer , caspase , genetics
Objectives SL4, a chalcone‐based compound, exhibits clearly inhibitory effects on HIF‐1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo . Here, studies were conducted to determine SL4's anti‐apoptotic effects and its underlying mechanisms, in human cancer cells. Materials and methods Cytotoxicity, apoptotic induction and its involved mechanisms of SL 4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species ( ROS ) and mitogen‐activated protein kinase ( MAPK ) signalling in SL 4‐induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells. Results SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA‐MB‐435 cells by activating procaspase‐8, ‐9 and ‐3, and down‐regulating expression levels of XIAP , but did not affect HIF ‐1 apoptosis‐related targets, Survivin and Bcl‐X L . Further study showed that SL 4 also reduced mitochondrial membrane potential and promoted generation of ROS . ROS generation and apoptotic induction by SL 4 were blocked by NAC , a scavenger of ROS , suggesting SL 4‐induced apoptosis via ROS accumulation. We also found that MAPK s, JNK and p38, but not ERK 1/2, to be critical mediators in SL 4‐induced apoptosis. SP 600125 and SB 203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL 4. Moreover, anti‐oxidant NAC blocked activation of JNK and p38 induced by SL 4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment. Conclusions These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics.