Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies
Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD<sup>+</sup> production. Despite the high efficacy of...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/4/1897 |
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| author | Paulina Biniecka Saki Matsumoto Axel Belotti Jessie Joussot Jian Fei Bai Somi Reddy Majjigapu Paul Thoueille Dany Spaggiari Vincent Desfontaine Francesco Piacente Santina Bruzzone Michele Cea Laurent A. Decosterd Pierre Vogel Alessio Nencioni Michel A. Duchosal Aimable Nahimana |
| author_facet | Paulina Biniecka Saki Matsumoto Axel Belotti Jessie Joussot Jian Fei Bai Somi Reddy Majjigapu Paul Thoueille Dany Spaggiari Vincent Desfontaine Francesco Piacente Santina Bruzzone Michele Cea Laurent A. Decosterd Pierre Vogel Alessio Nencioni Michel A. Duchosal Aimable Nahimana |
| author_sort | Paulina Biniecka |
| collection | DOAJ |
| description | Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD<sup>+</sup> production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., <b>FK866</b> (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, <b>JJ08</b>, <b>FEI191</b> and <b>FEI199</b>, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD<sup>+</sup> and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD<sup>+</sup> precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with <b>JJ08</b>, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor <b>JJ08</b> and highlight a strong interest for further evaluation of this compound in hematological malignancies. |
| first_indexed | 2024-03-11T08:21:13Z |
| format | Article |
| id | doaj.art-a934d28d76cf415f8074ec99c1403245 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T08:21:13Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a934d28d76cf415f8074ec99c14032452023-11-16T22:24:44ZengMDPI AGMolecules1420-30492023-02-01284189710.3390/molecules28041897Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological MalignanciesPaulina Biniecka0Saki Matsumoto1Axel Belotti2Jessie Joussot3Jian Fei Bai4Somi Reddy Majjigapu5Paul Thoueille6Dany Spaggiari7Vincent Desfontaine8Francesco Piacente9Santina Bruzzone10Michele Cea11Laurent A. Decosterd12Pierre Vogel13Alessio Nencioni14Michel A. Duchosal15Aimable Nahimana16Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandCentral Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandCentral Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandLaboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, SwitzerlandLaboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, SwitzerlandLaboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, SwitzerlandService and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandService and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandService and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, 16132 Genoa, ItalyDepartment of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, ItalyService and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandLaboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, SwitzerlandDepartment of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, ItalyCentral Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandCentral Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, SwitzerlandTargeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD<sup>+</sup> production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., <b>FK866</b> (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, <b>JJ08</b>, <b>FEI191</b> and <b>FEI199</b>, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD<sup>+</sup> and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD<sup>+</sup> precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with <b>JJ08</b>, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor <b>JJ08</b> and highlight a strong interest for further evaluation of this compound in hematological malignancies.https://www.mdpi.com/1420-3049/28/4/1897NAMPT inhibitorNADanticancerleukemialymphomamultiple myeloma |
| spellingShingle | Paulina Biniecka Saki Matsumoto Axel Belotti Jessie Joussot Jian Fei Bai Somi Reddy Majjigapu Paul Thoueille Dany Spaggiari Vincent Desfontaine Francesco Piacente Santina Bruzzone Michele Cea Laurent A. Decosterd Pierre Vogel Alessio Nencioni Michel A. Duchosal Aimable Nahimana Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies Molecules NAMPT inhibitor NAD anticancer leukemia lymphoma multiple myeloma |
| title | Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies |
| title_full | Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies |
| title_fullStr | Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies |
| title_full_unstemmed | Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies |
| title_short | Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies |
| title_sort | anticancer activities of novel nicotinamide phosphoribosyltransferase inhibitors in hematological malignancies |
| topic | NAMPT inhibitor NAD anticancer leukemia lymphoma multiple myeloma |
| url | https://www.mdpi.com/1420-3049/28/4/1897 |
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