Anti-cancer Activity Of Piperlongumine In Glioma And Leukemia Via Accumulation Of ROS

Piperlongumine (PL), a biological active alkaloid isolated from the long pepper, is recently found to kill cancer cells selectively and effectively via targeting to reactive oxygen species (ROS) responses.To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration, a process directly contribute to cancer invasion and malignancy. PL at5or10μM effectively inhibited the migration of human glioma (LN229), hepatocelluar carcinoma (HepG2, Huh7), bladder cancer (T24) and cervical cancer (Hela) cells but not normal astrocytes in vitro in the scratch-wound culture model. PL did not alter EdU+-cells in our model. PL increased ROS (measured by DCFH-DA), reduced glutathione, activated p38and JNK, increased IκBαand suppressed NFκB in LN229cells after scratching. All the biological effects of PL in scratched LN229cells could be completely abolished by the antioxidant N-acetyl-L-cysteine (NAC). Pharmacological administration of specific p38(SB203580) or JNK (SP600125) inhibitors significantly reduced the inhibitory effects of PL on LN229cell migration in both scratch-wound and transwell models. PL prevented the deformation of migrated LN229cells while NAC, SB203580or SP600125reversed PL-induced morphological changes of migrated cells in transwell assays. Additionally, a decrease of Cdc2and Cdc25C expression, which correlated with cell cycle arrest, was observed in PL-treated LN229cells, and this decrease was blocked by pretreatment of NAC. LC3expression was also regulated by PL and NAC in LN229cells.These results suggest potential therapeutic effects of PL by suppressing tumor invasion and metastasis, arresting cell cycle, inducing autophagy, which were particularly important for the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM) in the brain. Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. PL selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL killed cells from peripheral blood samples of leukemia patients via accumulating reactive oxygen species (ROS) to activate JNK and p38.PL at10and20μM could induce severe cell death in cells from leukemia patients. PL elevated ROS prominently levels in leukemia samples. Antioxidant NAC completely reversed PL-induced ROS accumulation and prevented cell death in leukemia cells. In leukemia cells, PL-treatment activated JNK and p38. These activations could be blocked by NAC pre-treatment. JNK and p38specific inhibitors, SB203580and SP600125respectively, significantly blocked the cytotoxic effects of PL in leukemia cells.Our data suggests that PL may have therapeutic potential for leukemia via accumulation of ROS, p38and JNK activation were involved in.