Impact of MAPK and PI3K/AKT signaling pathways on Malabaricone-A induced cytotoxicity in U937, a histiocytic lymphoma cell line

• MAL-A caused an up-regulation of MAPK (p38 and JNK).
• MAL-A caused a down-regulation of the PI3K/AKT/mTOR pathway.
• Inhibition of p38 and JNK decreased the cytotoxicity of MAL-A and its generation of reactive oxygen species.
• Inhibition of the PI3K/AKT pathway increased the cytotoxicity of MAL-A and its generation of reactive oxygen species.

Intrinsically cancer cells have higher basal levels of reactive oxygen species (ROS), which when augmented by pro-oxidants such as Malabaricone-A (MAL-A) triggers apoptotic cell death, secondary to ‘turning on’ of the apoptosis related cell signaling pathways. The effects of MAL-A upon key inflammation related signaling molecules were evaluated by western blotting in U937, a histiocytic lymphoma derived cell line. The impact of inhibitors of the pro-apoptotic MAPK and anti-apoptotic PI3K/AKT signaling pathways upon MAL-A induced cytotoxicity and generation of ROS was evaluated by a cell viability assay and flow cytometry respectively in two hematopoietic cell lines, U937 and MOLT3. MAL-A enhanced phosphorylation of the components of the pro-apoptotic pathway, namely ASK1, p38 and JNK. Alongside, MAL-A decreased the phosphorylation of AKT and mTOR. The cytotoxicity of MAL-A was attenuated by inhibitors of p38 and JNK, whereas its cytotoxic potential was enhanced in the presence of a PI3K/AKT inhibitor. Similarly, MAL-A mediated generation of ROS was decreased by inhibitors of p38MAPK and JNK, whereas the PI3K/AKT inhibitor potentiated its generation of ROS. Taken together, MAL-A mediated its cytotoxicity by enhanced generation of ROS via modulation of the apoptosis related cellular signaling pathways and tilting the balance towards a pro-apoptotic scenario. This was achieved via an up-regulation of MAPK (p38 and JNK) along with down-regulation of the PI3K/AKT/mTOR pathway indicating that manipulation of these pathways by compounds such as MAL-A are promising therapeutic targets, worthy of future pharmacological consideration.

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