Abstract
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.
Highlights
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide [1]
Mitogen-activated protein kinase (MAPK) family, which mainly consists of extracellular-signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 are www.impactjournals.com/oncotarget mediators of intracellular signals involved in the regulation of processes including cell growth and apoptosis [35]
Cytotoxic effects of CT on gastric cancer (GC) cells are attributable to mitochondrial-mediated apoptosis
Summary
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide [1]. ROS such as oxygen ions, superoxide and hydrogen peroxide (H2O2) or hydroxyl radicals which mediate intracellular signaling cascades may trigger redox signaling pathways, such as oxidative stress, apoptosis, and cell cycle arrest [7, 8]. The antitumor effect of CT may be attributed to accumulated ROS leading to p-JNK and p-p38 increasing and p-ERK, p-Akt and p-STAT3 decreasing, induced apoptosis and G2/M phase arrest. These data suggest that CT is worthy of further study for the treatment of GC
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