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Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present herein the preparation of three libraries of new inhibitors containing (pyridin-3-yl)triazole, (pyridin-3-yl)thiourea and (pyridin-3/4-yl)cyanoguanidine as cap/connecting unit and a furyl group at the tail position of the compound. Antiproliferative activity in vitro was evaluated on a panel of solid and haematological cancer cell lines and most of the synthesized compounds showed nanomolar or sub-nanomolar cytotoxic activity in MiaPaCa-2 (pancreatic cancer), ML2 (acute myeloid leukemia), JRKT (acute lymphobalistic leukemia), NMLW (Burkitt lymphoma), RPMI8226 (multiple myeloma) and NB4 (acute myeloid leukemia), with lower IC50 values than those reported for FK866. Notably, compounds 35a, 39a and 47 showed cytotoxic activity against ML2 with IC50 = 18, 46 and 49 pM, and IC50 towards MiaPaCa-2 of 0.005, 0.455 and 2.81 nM, respectively. Moreover, their role on the NAD+ synthetic pathway was demonstrated by the NAMPT inhibition assay. Finally, the intracellular NAD+ depletion was confirmed in vitro to induced ROS accumulation that cause a time-dependent mitochondrial membrane depolarization, leading to ATP loss and cell death.

Cancer cells must reprogram their metabolism to sustain their continuous growth and proliferation. They rely on fast nicotinamide adenine dinucleotide (NAD+) turnover for their energy supply, which is crucial for their survival. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme involved in the production of NAD+. The inhibition of NAMPT induces NAD+ depletion and is a therapeutic strategy to selectively eliminate malignant cells highly dependent on NAD+. Until now, several NAMPT inhibitors have been developed and, despite their high efficacy in preclinical studies, their clinical activity was limited. Therefore, there is still a need to synthesize novel more potent NAMPT inhibitors and/or to specifically target them to cancer cells. In this work, new NAMPT inhibitors were characterized for their biological activities in vitro and in vivo on haematological malignancies. Moreover, few selected NAMPT inhibitors were conjugated to an anti-CD138 antibody, targeting inhibitors to multiple myeloma cells. All tested compounds exhibited low nanomolar cytotoxicity against various haematological cancer cell lines. They depleted NAD+ after 24 hours of drug treatment, followed by ATP depletion and mitochondrial membrane depolarization, what finally led to various types of cell death (apoptosis and necrosis). Treatments with NAMPT inhibitors caused time-dependent reactive oxygen species (ROS) production that was rescued by catalase (CAT). Unfortunately, the most potent compounds in vitro (i.e., FEI199) did not translate their efficacy in vivo. Indeed, among all compounds (JJ08, FEI191, FEI199) administered into mouse xenograft model of human Burkitt lymphoma only JJ08 completely eradicated tumour growth. Moreover, the pharmacokinetics (PK) profile of JJ08 was like that of APO866. Some of the synthesized analogues were further modified to be attached to an anti-CD138 antibody to create antibody-drug-conjugates (ADCs). CD138 is an antigen selectively overex

A newly produced hierarchical, nanoporous carbon (HNC) material is studied for the first time in a biological model. The material consists of uniform particles and is characterized by a mean diameter <150 nm, a high specific surface area of 1,000 m2/g, well-developed porosity, and high electrical conductivity. These unique properties and ability to transfer charge create a possibility of employing HNC as a moderator of tumor cell growth. As the charge of HNC may interfere with cell membranes by adhesion and by bonding with cell receptors, it may block the supply of nutrients. The interactions of HNC with the U87 cells can also lead to the excessive generation of reactive oxygen species (ROS) and activate apoptotic mechanisms in cancer cells. The investigation was performed using U87 human glioblastoma and PCS-201–010 normal fibroblast cell lines, where cell morphology and ultrastructure, viability, ROS production, type of cell death, mitochondrial transmembrane potential, and the expression of genes engaged in apoptosis pathways are studied. The results demonstrate that cytotoxicity of HNC particles increases with concentration from 5 to 100 μg/mL by activation of apoptosis through the mitochondrial pathway, without inducing necrosis. Our research indicates the potential applicability of HNC in cancer therapy.

SÅ‚awomir Jaworski,1 Paulina Biniecka,1 Å»aneta Bugajska,1 Karolina Daniluk,1 SÅ‚awomir Dyjak,2 Barbara Strojny,1 Marta Kutwin,1 Mateusz Wierzbicki,1 Marta Grodzik,1 André Chwalibog3 1Division of Nanobiotechnology, Warsaw University of Life Science, 2Faculty of Advanced Technologies and Chemistry, Military University of Technology, Warsaw, Poland; 3Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark Abstract: A newly produced hierarchical, nanoporous carbon (HNC) material is studied for the first time in a biological model. The material consists of uniform particles and is characterized by a mean diameter <150 nm, a high specific surface area of 1,000 m2/g, well-developed porosity, and high electrical conductivity. These unique properties and ability to transfer charge create a possibility of employing HNC as a moderator of tumor cell growth. As the charge of HNC may interfere with cell membranes by adhesion and by bonding with cell receptors, it may block the supply of nutrients. The interactions of HNC with the U87 cells can also lead to the excessive generation of reactive oxygen species (ROS) and activate apoptotic mechanisms in cancer cells. The investigation was performed using U87 human glioblastoma and PCS-201–010 normal fibroblast cell lines, where cell morphology and ultrastructure, viability, ROS production, type of cell death, mitochondrial transmembrane potential, and the expression of genes engaged in apoptosis pathways are studied. The results demonstrate that cytotoxicity of HNC particles increases with concentration from 5 to 100 µg/mL by activation of apoptosis through the mitochondrial pathway, without inducing necrosis. Our research indicates the potential applicability of HNC in cancer therapy. Keywords: toxicity, glioblastoma, graphenic carbon material, nanoparticles, U87 cells, fibroblast cells