p53 is frequently mutated by genetic alternation or suppressed by various kinds of cellular signaling pathways in human cancers. Recently, we have revealed that p53 is suppressed and eliminated from cells by direct binding with oncogenic K-Ras-induced Snail. On the basis of the fact, we generated specific inhibitors against p53-Snail binding (GN25 and GN29). These chemicals can induce p53 expression and functions in K-Ras-mutated cells. However, it does not show cytotoxic effect on normal cells or K-Raswild-type cells. Moreover, GN25 can selectively activate wild-type p53 in p53 WT/MT cancer cells. But single allelic mt p53 containing cell line, Panc-1, does not respond to our chemical. In vivo xenograft test also supports the antitumor effect of GN25 in K-Ras-mutated cell lines. These results suggest that our compounds are strong candidate for anticancer drug against K-Ras-initiated human cancers including pancreatic and lung cancers.
Cryptotanshinone (CT), isolated from the plant Salvia miltiorrhiza Bunge, has been reported to have potential anticancer effects on human prostate and breast cancer cells. However, the mechanisms of action of CT on gastric cancer (GC) cells are not well understood. Here we investigated the antitumor effects of CT on GC cells and its possible molecular mechanism. We found CT suppressed viability of twelve GC cell lines in a dose-dependent manner. CT induced cell cycle arrest at the G2/M phase and mitochondrial apoptosis accompanying the accumulation of reactive oxygen species (ROS). Pretreatment with ROS inhibitor N-acetyl-L-cysteine (NAC) blocked CT-induced apoptosis. CT increased p-JNK and p-p38, and decreased p-ERK and p-STAT3 protein expression, these effects were prevented by NAC. Furthermore, a xenograft assay showed that CT significantly inhibited MKN-45 cell-induced tumor growth in vivo by increasing expression of pro-apoptotic proteins (p-JNK, p-38 and cleaved-caspase-3) and reducing expression of anti-apoptotic proteins (p-ERK and p-STAT3) without adverse effects on nude mice weight. In conclusion, CT induced apoptosis and cell cycle arrest in GC cells via ROS-mediated MAPK and AKT signaling pathways, and this CT may be a useful compound for the developing anticancer agents for GC.
Isoorientin (ISO) is a naturally occurring C-glycosyl flavone that has various pharmacological properties, such as anti-bacterial and anti-inflammatory effects. However, its underlying molecular mechanisms in human lung cancer cells remain unknown. In the present study, the effects of ISO on the induction of apoptosis and relative molecular mechanisms in A549 human lung cancer cells were investigated. The results of Cell Counting Kit-8 assay (CCK-8) indicated that ISO exerted significant cytotoxic effects on 3 lung cancer cell lines, but had no obvious side-effects on normal cells. Moreover, flow cytometry and western blot analysis revealed that ISO induced mitochondrial-dependent apoptosis by reducing mitochondrial membrane potential. ISO also increased the expression levels of Bax, cleaved-caspase-3 (cle-cas-3) and poly(ADP-ribose) polymerase (PARP; cle-PARP), and decreased the expression levels of Bcl-2 in A549 cells. Furthermore, ISO induced G2/M cell cycle arrest by decreasing the expression levels of cyclin B1 and CDK1/2, and increasing the expression levels of p21 and p27 in A549 cells. As the duration of ISO treatment increased, intracellular reactive oxygen species (ROS) levels in A549 cells also increased. However, pre-treatment of the cells with the ROS scavenger, N-acetylcysteine (NAC), inhibited ISO-induced apoptosis. In addition, ISO increased the expression levels of p-p38, p-JNK and IκB-α; and decreased the expression levels of p-extracellular signal-regulated kinase (ERK), p-signal transducer and activator of transcription (STAT)3, p-nuclear factor (NF)-κB, NF-κB and p-IκB; these effects were induced by mitogen-activated protein kinase (MAPK) inhibitors and blocked by NAC. Taken together, the results of the present study indicate that ISO induces the apoptosis of A549 lung cancer cells via the ROS-mediated MAPK/STAT3/NF-κB signaling pathway, and thus may be a potential drug for use in the treatment of lung cancer.
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