APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells.

Abstract

PURPOSE:

The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, APO866, has been previously shown to have antileukemic activity in preclinical models, but its cytotoxicity in primary leukemia cells is frequently limited. The success of current antileukemic treatments is reduced by the occurrence of multidrug resistance, which, in turn, is mediated by membrane transport proteins, such as P-glycoprotein-1 (Pgp). Here, we evaluated the antileukemic effects of APO866 in combination with Pgp inhibitors and studied the mechanisms underlying the interaction between these two types of agents.

EXPERIMENTAL DESIGN:

The effects of APO866 with or without Pgp inhibitors were tested on the viability of leukemia cell lines, primary leukemia cells (AML, n = 6; B-CLL, n = 19), and healthy leukocytes. Intracellular nicotinamide adenine dinucleotide (NAD(+)) and ATP levels, mitochondrial transmembrane potential (ΔΨ(m)), markers of apoptosis and of endoplasmic reticulum (ER) stress were evaluated.

RESULTS:

The combination of APO866 with Pgp inhibitors resulted in a synergistic cytotoxic effect in leukemia cells, while sparing normal CD34(+) progenitor cells and peripheral blood mononuclear cells. Combining Pgp inhibitors with APO866 led to increased intracellular APO866 levels, compounded NAD(+) and ATP shortage, and induced ΔΨ(m) dissipation. Notably, APO866, Pgp inhibitors and, to a much higher extent, their combination induced ER stress and ER stress inhibition strongly reduced the activity of these treatments.

CONCLUSIONS:

APO866 and Pgp inhibitors show a strong synergistic cooperation in leukemia cells, including acute myelogenous leukemia (AML) and B-cell chronic lymphocytic leukemia (B-CLL) samples. Further evaluations of the combination of these agents in clinical setting should be considered.

• Authors: Antonia Cagnetta, Irene Caffa, Chirag Acharya, Debora Soncini, Prakrati Acharya, Sophia Adamia, Ivana Pierri, Micaela Bergamaschi, Anna Garuti, Giulio Fraternali, Luca Mastracci, Alessandro Provenzani, Chiara Zucal, Gianluca Damonte, Annalisa Salis, Fabrizio Montecucco, Franco Patrone, Alberto Ballestrero, Santina Bruzzone, Marco Gobbi, Alessio Nencioni, Michele Cea
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 17 Pg. 3934-45 (Sep 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25964294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Acrylamides
• Antineoplastic Agents
• Immunoglobulin Heavy Chains
• N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
• Piperidines
• NAD
• Niacinamide
• Niacin
• Cyclosporine
• Adenosine Triphosphate
• Nicotinamide Phosphoribosyltransferase

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, metabolism)
• Acrylamides (pharmacology)
• Adenosine Triphosphate (metabolism)
• Aged
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromosome Aberrations
• Cyclosporine (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Gene Expression
• Humans
• Immunoglobulin Heavy Chains (genetics)
• Leukemia (genetics, metabolism, mortality, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Middle Aged
• Mitochondria (drug effects, metabolism)
• Mutation
• NAD (metabolism)
• Neoplasm Staging
• Niacin (pharmacology)
• Niacinamide (pharmacology)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, genetics, metabolism)
• Piperidines (pharmacology)
• Primary Cell Culture
• Prognosis
• Tumor Cells, Cultured
• Unfolded Protein Response (drug effects)