Abstract 1996
Background
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1, and has a poor outcome. New molecular targets for the prevention and treatment of ATL are urgently needed. We previously reported that Sirtuin 1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, is highly expressed in primary acute-type ATL cells. NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates Sirtuin 1 activity. Here, we examined the expression and effects of inhibiting NAMPT, a rate-limiting.
Methods
Peripheral blood mononuclear cells from ATL patients were carried out in accordance with the guidelines of the Committees for Ethical Review of Research involving Human Subjects at Kagoshima University Hospital. Cell viability was evaluated in the S1T cell line derived from an ATL patient, MT-2 cell line derived from normal human leukocytes transformed by leukemic T-cells from an ATL patient, and primary ATL cells. Animal experiments were approved by the Animal Care and Use Committee of Rakuno Gakuen University in accordance with the Guide for the Care and Use of Laboratory Animals.
Results
Peripheral blood mononuclear cells from acute-type ATL patients expressed significantly higher NAMPT protein levels than cells from healthy controls. FK866, a NAMPT inhibitor, induced apoptosis in fresh ATL cells ex vivo and HTLV-1-infected T-cell lines in vitro, which was accompanied by NAD+ depletion, activation of caspases, DNA fragmentation, and disruption of mitochondrial transmembrane potential. A pan-caspase inhibitor failed to prevent the FK866-induced cell death, while FK866 increased endonuclease G, a caspase-independent cell death mediator. Intriguingly, FK866 activated autophagy, revealed by increased LC3-II protein levels and autophagic flux. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased human ATL tumor xenograft growth in immunodeficient mice.
Conclusions
These results demonstrate that NAMPT inhibition induces autophagy and caspase-dependent and -independent cell death in ATL cells, suggesting a novel therapeutic strategy for patients with this fatal disease.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3620 - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours
Presenter: Wolfgang Wick
Session: Poster Display session 1
Resources:
Abstract
5465 - Proof of concept clinical study by US-guided intratumor injection of VCN-01, an oncolytic adenovirus expressing hyaluronidase in patients with pancreatic cancer
Presenter: Manuel Hidalgo
Session: Poster Display session 1
Resources:
Abstract
2555 - A Phase 1a/b first-in-human, open-label, dose-escalation, safety, PK and PD study of TP-0903 in solid tumors
Presenter: John Sarantopoulos
Session: Poster Display session 1
Resources:
Abstract
3533 - First in human phase 1/2a study of PEN-866, a Heat Shock Protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumors: Phase 1 results
Presenter: Johanna Bendell
Session: Poster Display session 1
Resources:
Abstract
4114 - A Phase I Open-Label, Non-Randomized Study of Recombinant Super-Compound Interferon (rSIFN-co) In Patients with Advanced Solid Tumors
Presenter: Amanda Seet
Session: Poster Display session 1
Resources:
Abstract
2537 - Evaluation of Pharmacodynamic (PD) Biomarkers in Advanced Cancer Patients Treated with Oxidative Phosphorylation (OXPHOS) Inhibitor, OPC-317 (OPC)
Presenter: Jie Qing Eu
Session: Poster Display session 1
Resources:
Abstract
5764 - Pharmacokinetic (PK) assessment of BT1718: A phase 1/2a study of BT1718, a first in class Bicycle Toxin Conjugate (BTC), in patients (pts) with advanced solid tumours
Presenter: Natalie Cook
Session: Poster Display session 1
Resources:
Abstract
2683 - A phase I open label dose escalation trial evaluating VT1021 in patients with advanced solid tumors.
Presenter: Wael Harb
Session: Poster Display session 1
Resources:
Abstract
3609 - Interim Results from Trial of SL-801, a Novel XPO-1 Inhibitor, in Patients with Advanced Solid Tumors
Presenter: Judy Wang
Session: Poster Display session 1
Resources:
Abstract
3485 - Phase 1 Trial of Fruquintinib in Patients with Advanced Solid Tumors: Results of the Dose Escalation Phase
Presenter: Andrea Wang-Gillam
Session: Poster Display session 1
Resources:
Abstract