A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα
BackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antago...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-11-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1488722/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846156454661193728 |
|---|---|
| author | Alessandra Ammazzalorso Stefania Tacconelli Annalisa Contursi Ulrika Hofling Carmen Cerchia Sara Di Berardino Alessandra De Michele Rosa Amoroso Antonio Lavecchia Paola Patrignani |
| author_facet | Alessandra Ammazzalorso Stefania Tacconelli Annalisa Contursi Ulrika Hofling Carmen Cerchia Sara Di Berardino Alessandra De Michele Rosa Amoroso Antonio Lavecchia Paola Patrignani |
| author_sort | Alessandra Ammazzalorso |
| collection | DOAJ |
| description | BackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models.MethodsAA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent.ResultsIn HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E2 generation with an IC50 of 0.10 (95% CI: 0.05–0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells.ConclusionWe have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed. |
| format | Article |
| id | doaj-art-5c7eb75e16cc4e4bb13aaa4e81dd9bb1 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-5c7eb75e16cc4e4bb13aaa4e81dd9bb12024-11-26T04:26:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-11-011510.3389/fphar.2024.14887221488722A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARαAlessandra Ammazzalorso0Stefania Tacconelli1Annalisa Contursi2Ulrika Hofling3Carmen Cerchia4Sara Di Berardino5Alessandra De Michele6Rosa Amoroso7Antonio Lavecchia8Paola Patrignani9Department of Pharmacy, “G. d’Annunzio” University, Chieti, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalyDepartment of Pharmaceutical and Toxicological Chemistry, University of Naples “Federico II”, Naples, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalyDepartment of Pharmacy, “G. d’Annunzio” University, Chieti, ItalyDepartment of Pharmaceutical and Toxicological Chemistry, University of Naples “Federico II”, Naples, ItalySystems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), and Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University, Chieti, ItalyBackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models.MethodsAA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent.ResultsIn HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E2 generation with an IC50 of 0.10 (95% CI: 0.05–0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells.ConclusionWe have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed.https://www.frontiersin.org/articles/10.3389/fphar.2024.1488722/fullCOX-2PPARαwhole bloodNSAIDscoxibslipidomics of eicosanoids |
| spellingShingle | Alessandra Ammazzalorso Stefania Tacconelli Annalisa Contursi Ulrika Hofling Carmen Cerchia Sara Di Berardino Alessandra De Michele Rosa Amoroso Antonio Lavecchia Paola Patrignani A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα Frontiers in Pharmacology COX-2 PPARα whole blood NSAIDs coxibs lipidomics of eicosanoids |
| title | A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα |
| title_full | A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα |
| title_fullStr | A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα |
| title_full_unstemmed | A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα |
| title_short | A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα |
| title_sort | sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase 2 and pparα |
| topic | COX-2 PPARα whole blood NSAIDs coxibs lipidomics of eicosanoids |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1488722/full |
| work_keys_str_mv | AT alessandraammazzalorso asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT stefaniatacconelli asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT annalisacontursi asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT ulrikahofling asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT carmencerchia asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT saradiberardino asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT alessandrademichele asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT rosaamoroso asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT antoniolavecchia asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT paolapatrignani asulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT alessandraammazzalorso sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT stefaniatacconelli sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT annalisacontursi sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT ulrikahofling sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT carmencerchia sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT saradiberardino sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT alessandrademichele sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT rosaamoroso sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT antoniolavecchia sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara AT paolapatrignani sulfonimidederivativeofbezafibrateasadualinhibitorofcyclooxygenase2andppara |