Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies
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
Affiliations
Paulina Biniecka
Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Saki Matsumoto
Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Axel Belotti
Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Jessie Joussot
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland
Jian Fei Bai
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland
Somi Reddy Majjigapu
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland
Paul Thoueille
Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Dany Spaggiari
Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Vincent Desfontaine
Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Francesco Piacente
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, 16132 Genoa, Italy
Santina Bruzzone
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, 16132 Genoa, Italy
Michele Cea
Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
Laurent A. Decosterd
Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Pierre Vogel
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland
Alessio Nencioni
Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
Michel A. Duchosal
Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Aimable Nahimana
Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
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+ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD+ 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+ 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 JJ08, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor JJ08 and highlight a strong interest for further evaluation of this compound in hematological malignancies.
