Overexpression of NAMPT in adult T-cell leukemia/lymphoma patients and anti-tumor activity of a NAMPT inhibitor in vivo

Date 21 October 2018
Event ESMO 2018 Congress
Session Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Topics Leukaemia
Lymphomas
Cancer Biology
Presenter Tomohiro Kozako
Citation Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268
Authors T. Kozako1, T. Ohsugi2, M. Yoshimitsu3, Y. Uchida3, K. Ishitsuka3, K. Naho1, A. Aikawa1, S. Honda1
  • 1Department Of Biochemistry, Faculty Of Pharmaceutical Sciences, Fukuoka University, 814-0180 - FUKUOKA/JP
  • 2Department Of Hematology And Immunology, Rakuno Gakuen University, 069-8501 - Ebethu/JP
  • 3Center For Chronic Viral Diseases, Kagoshima University,, Kagoshima/JP

Abstract

Background

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus (HTLV) that has poor outcomes. New molecular targets for prevention and treatment of ATL are urgently needed. We reported that SIRT1, 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 SIRT1 activity. We examined the expression and inhibition of NAMPT, a rate-limiting enzyme in NAD+ biosynthesis, in ATL cells.

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 cell lines and fresh ATL cells, accompanied by caspase activation, DNA fragmentation, and mitochondrial transmembrane potential disruption in vitro. 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. 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

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.