Ferroptosis is an iron-mediated regulated cell death initiated by excessive membrane lipid peroxideaccumulation.The intimate interplay between ferroptosis and lipid metabolism suggests that modulatinglipid metabolism ...Ferroptosis is an iron-mediated regulated cell death initiated by excessive membrane lipid peroxideaccumulation.The intimate interplay between ferroptosis and lipid metabolism suggests that modulatinglipid metabolism and activating ferroptosis may represent a broader cancer therapeutic space.Herein,two fibrate lipid-modulating agents,fenofibric acid and ciprofibrate,were employed to functionalize theclinical drug cisplatin through a Pt(Ⅳ)prodrug strategy,affording four fibrate-Pt(Ⅳ)anticancer prodrugs,compounds 1-4,with prominent anticancer activity and ferroptosis induction.The representative com-pounds,1 and 3,exhibited antiproliferative activity up to 140-and 90-fold greater than cisplatin,respectively.Our data demonstrated that fibrate-Pt(Ⅳ)prodrugs accumulated in A549 cells much higher than cisplatin,fol-lowed by a dramatic decrease in intracellular lipid content,elevated reactive oxygen species(ROS)levels,dis-ruption of the mitochondrial transmembrane potential,and remarkable proliferation inhibition.Moreover,ourresults revealed that fibrate-Pt(Ⅳ)prodrugs not only induced DNA damage,apoptosis,and cell cycle arrest,but also led to increases in lipid peroxides,ferrous ions,and malondialdehyde(MDA),as well as a decrease inglutathione,which triggers ferroptosis by suppressing the system Xc^(−)/GSH/GPX4 antioxidant defense axis andstimulation of the iron axis.Our results emphasize that combining lipid metabolism regulation with ferroptosisto develop new platinum-based anticancer agents can produce excellent multi-action anticancer activities,which may represent a promising cancer treatment modality.展开更多
基金supported by the National Natural Science Foundation of China(No.22377090 and 21977080)the Tianjin Municipal Education Commission Science Foundation(No.2021ZD039).
文摘Ferroptosis is an iron-mediated regulated cell death initiated by excessive membrane lipid peroxideaccumulation.The intimate interplay between ferroptosis and lipid metabolism suggests that modulatinglipid metabolism and activating ferroptosis may represent a broader cancer therapeutic space.Herein,two fibrate lipid-modulating agents,fenofibric acid and ciprofibrate,were employed to functionalize theclinical drug cisplatin through a Pt(Ⅳ)prodrug strategy,affording four fibrate-Pt(Ⅳ)anticancer prodrugs,compounds 1-4,with prominent anticancer activity and ferroptosis induction.The representative com-pounds,1 and 3,exhibited antiproliferative activity up to 140-and 90-fold greater than cisplatin,respectively.Our data demonstrated that fibrate-Pt(Ⅳ)prodrugs accumulated in A549 cells much higher than cisplatin,fol-lowed by a dramatic decrease in intracellular lipid content,elevated reactive oxygen species(ROS)levels,dis-ruption of the mitochondrial transmembrane potential,and remarkable proliferation inhibition.Moreover,ourresults revealed that fibrate-Pt(Ⅳ)prodrugs not only induced DNA damage,apoptosis,and cell cycle arrest,but also led to increases in lipid peroxides,ferrous ions,and malondialdehyde(MDA),as well as a decrease inglutathione,which triggers ferroptosis by suppressing the system Xc^(−)/GSH/GPX4 antioxidant defense axis andstimulation of the iron axis.Our results emphasize that combining lipid metabolism regulation with ferroptosisto develop new platinum-based anticancer agents can produce excellent multi-action anticancer activities,which may represent a promising cancer treatment modality.
