Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2-C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2-C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.

Automated summary

Chemotherapeutic agents containing the Michael acceptor are potent anticancer molecules that promote intracellular ROS generation. The study synthesized PL analogs with electrophilic groups at the C2-C3 double bond, which played a key role in cytotoxicity, and substituents on the aromatic ring partly contributed to anticancer activity. Additionally, PL analogs inhibited TrxR irreversibly and increased ROS generation, leading to disruption of redox balance, lipid peroxidation, loss of MMP, cell cycle arrest, and ultimately apoptosis in A549 cell line.