Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan...Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide(CX-5461),the first Pol Ⅰ selective inhibitor with the multitargeting property and synthetical lethality in homologous recombination(HR)deficient cancers,to modify cisplatin,affording two monofunctional platinum Pol Ⅰ selective inhibitors[PtCl(NH_(3))_(2)(LH1)]NO_(3)(P1-Q1)and[PtCl(NH_(3))_(2)(LH_(2))]NO_(3)(P1-Q2)[LH1=N-(3-(N-methylacetimidamido)propyl)-2-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide;LH2=2-(4-methyl-1,4-diazepan-1-yl)-N-(3-(N-methylacetimidamido)propyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide].Our data showed that P1-Q1 and P1-Q2 could preferentially target the Pol Ⅰ transcription machinery,overcome platinum drug resistance,and display more potent antiproliferative activity in BRCA1-deficient A549 cells.Mechanism studies demonstrated that P1-Q1 and P1-Q2 could effectively accumulate in cancer cells and nucleoli,selectively inhibit Pol Ⅰ transcription,stimulate nucleolar stress and p53 stabilization,increase intracellular ROS levels,disrupt the mitochondrial membrane potential,and inhibit migration and metastasis,which further lead to cell cycle arrest and apoptosis.Particularly,P1-Q1 could facilitate the formation and stabilization of R-loops,induce severe DNA damage,and trigger ATR/CHK1 and ATM/CHK2 kinase signaling cascades in BRCA1-deficient A549 cells,suggesting that defects in the HR pathway may exacerbate P1-Q1 induced DNA damage and cause synthetic lethality and apoptosis.Our data demonstrated that P1-Q1 and P1-Q2 are distinct from the clinical platinum anticancer drugs in their mechanism of action,and taking advantage of the selective Pol Ⅰ inhibition,multitargeting property,and synthetic lethality of CX-5461 in HR-deficient cancers to modify platinum-based agents might be a brand-new approach for cancer therapy.展开更多
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.21977080 and 21401141)the Tianjin Municipal Education Commission Science Foundation(No.2021ZD039).
文摘Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide(CX-5461),the first Pol Ⅰ selective inhibitor with the multitargeting property and synthetical lethality in homologous recombination(HR)deficient cancers,to modify cisplatin,affording two monofunctional platinum Pol Ⅰ selective inhibitors[PtCl(NH_(3))_(2)(LH1)]NO_(3)(P1-Q1)and[PtCl(NH_(3))_(2)(LH_(2))]NO_(3)(P1-Q2)[LH1=N-(3-(N-methylacetimidamido)propyl)-2-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide;LH2=2-(4-methyl-1,4-diazepan-1-yl)-N-(3-(N-methylacetimidamido)propyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide].Our data showed that P1-Q1 and P1-Q2 could preferentially target the Pol Ⅰ transcription machinery,overcome platinum drug resistance,and display more potent antiproliferative activity in BRCA1-deficient A549 cells.Mechanism studies demonstrated that P1-Q1 and P1-Q2 could effectively accumulate in cancer cells and nucleoli,selectively inhibit Pol Ⅰ transcription,stimulate nucleolar stress and p53 stabilization,increase intracellular ROS levels,disrupt the mitochondrial membrane potential,and inhibit migration and metastasis,which further lead to cell cycle arrest and apoptosis.Particularly,P1-Q1 could facilitate the formation and stabilization of R-loops,induce severe DNA damage,and trigger ATR/CHK1 and ATM/CHK2 kinase signaling cascades in BRCA1-deficient A549 cells,suggesting that defects in the HR pathway may exacerbate P1-Q1 induced DNA damage and cause synthetic lethality and apoptosis.Our data demonstrated that P1-Q1 and P1-Q2 are distinct from the clinical platinum anticancer drugs in their mechanism of action,and taking advantage of the selective Pol Ⅰ inhibition,multitargeting property,and synthetic lethality of CX-5461 in HR-deficient cancers to modify platinum-based agents might be a brand-new approach for cancer therapy.
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.
