APO866 increases antitumor activity of cyclosporin - A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells

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 GobbiAlessio Nencioni, Michele Cea

Research output: Contribution to journalArticle

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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 (Δψm), 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 Δψm 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.

Original languageEnglish
Pages (from-to)3934-3945
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number17
DOIs
Publication statusPublished - Sep 1 2015

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Endoplasmic Reticulum Stress
Cyclosporine
Leukemia
B-Cell Chronic Lymphocytic Leukemia
NAD
Acute Myeloid Leukemia
Adenosine Triphosphate
Nicotinamide Phosphoribosyltransferase
Membrane Transport Proteins
N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
Multiple Drug Resistance
P-glycoprotein 2
Membrane Potentials
Blood Cells
Leukocytes
Research Design
Stem Cells
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

APO866 increases antitumor activity of cyclosporin - A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells. / Cagnetta, Antonia; Caffa, Irene; Acharya, Chirag; Soncini, Debora; Acharya, Prakrati; Adamia, Sophia; Pierri, Ivana; Bergamaschi, Micaela; Garuti, Anna; Fraternali, Giulio; Mastracci, Luca; Provenzani, Alessandro; Zucal, Chiara; Damonte, Gianluca; Salis, Annalisa; Montecucco, Fabrizio; Patrone, Franco; Ballestrero, Alberto; Bruzzone, Santina; Gobbi, Marco; Nencioni, Alessio; Cea, Michele.

In: Clinical Cancer Research, Vol. 21, No. 17, 01.09.2015, p. 3934-3945.

Research output: Contribution to journalArticle

Cagnetta, A, Caffa, I, Acharya, C, Soncini, D, Acharya, P, Adamia, S, Pierri, I, Bergamaschi, M, Garuti, A, Fraternali, G, Mastracci, L, Provenzani, A, Zucal, C, Damonte, G, Salis, A, Montecucco, F, Patrone, F, Ballestrero, A, Bruzzone, S, Gobbi, M, Nencioni, A & Cea, M 2015, 'APO866 increases antitumor activity of cyclosporin - A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells', Clinical Cancer Research, vol. 21, no. 17, pp. 3934-3945. https://doi.org/10.1158/1078-0432.CCR-14-3023
Cagnetta, Antonia ; Caffa, Irene ; Acharya, Chirag ; Soncini, Debora ; Acharya, Prakrati ; Adamia, Sophia ; Pierri, Ivana ; Bergamaschi, Micaela ; Garuti, Anna ; Fraternali, Giulio ; Mastracci, Luca ; Provenzani, Alessandro ; Zucal, Chiara ; Damonte, Gianluca ; Salis, Annalisa ; Montecucco, Fabrizio ; Patrone, Franco ; Ballestrero, Alberto ; Bruzzone, Santina ; Gobbi, Marco ; Nencioni, Alessio ; Cea, Michele. / APO866 increases antitumor activity of cyclosporin - A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 17. pp. 3934-3945.
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T1 - APO866 increases antitumor activity of cyclosporin - A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells

AU - Cagnetta, Antonia

AU - Caffa, Irene

AU - Acharya, Chirag

AU - Soncini, Debora

AU - Acharya, Prakrati

AU - Adamia, Sophia

AU - Pierri, Ivana

AU - Bergamaschi, Micaela

AU - Garuti, Anna

AU - Fraternali, Giulio

AU - Mastracci, Luca

AU - Provenzani, Alessandro

AU - Zucal, Chiara

AU - Damonte, Gianluca

AU - Salis, Annalisa

AU - Montecucco, Fabrizio

AU - Patrone, Franco

AU - Ballestrero, Alberto

AU - Bruzzone, Santina

AU - Gobbi, Marco

AU - Nencioni, Alessio

AU - Cea, Michele

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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 (Δψm), 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 Δψm 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.

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