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

doi:10.3390/molecules28041897

Molecules (Feb 2023)

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

DOI: https://doi.org/10.3390/molecules28041897
Journal volume & issue: Vol. 28, no. 4
p. 1897

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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