PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines

Simona Ultimo, Carolina Simioni, Alberto M Martelli, Giorgio Zauli, Camilla Evangelisti, Claudio Celeghini, James A McCubrey, Giorgia Marisi, Paola Ulivi, Silvano Capitani, Luca M Neri

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110α BYL719 inhibitor and the dual p110γ/p110δ inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.

Original languageEnglish
Pages (from-to)23213-23227
Number of pages15
JournalOncotarget
Volume8
Issue number14
DOIs
Publication statusPublished - Apr 4 2017

Fingerprint

Chromosomes, Human, 4-5
Philadelphia Chromosome
Phosphatidylinositol 3-Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein Isoforms
Cell Line
bcr-abl Fusion Proteins
Pharmaceutical Preparations
Autophagy
Cell Survival
Phosphatidylinositol 3-Kinase
Apoptosis
B-Lymphoid Precursor Cells
Drug Combinations
Sirolimus
Flow Cytometry
Western Blotting
Phosphorylation
In Vitro Techniques
Growth

Keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Fusion Proteins, bcr-abl
  • Humans
  • Imatinib Mesylate
  • Isoenzymes
  • Isoquinolines
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Purines
  • Pyrazoles
  • Pyrimidines
  • Thiazoles
  • Triazines
  • Journal Article

Cite this

PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines. / Ultimo, Simona; Simioni, Carolina; Martelli, Alberto M; Zauli, Giorgio; Evangelisti, Camilla; Celeghini, Claudio; McCubrey, James A; Marisi, Giorgia; Ulivi, Paola; Capitani, Silvano; Neri, Luca M.

In: Oncotarget, Vol. 8, No. 14, 04.04.2017, p. 23213-23227.

Research output: Contribution to journalArticle

Ultimo, Simona ; Simioni, Carolina ; Martelli, Alberto M ; Zauli, Giorgio ; Evangelisti, Camilla ; Celeghini, Claudio ; McCubrey, James A ; Marisi, Giorgia ; Ulivi, Paola ; Capitani, Silvano ; Neri, Luca M. / PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines. In: Oncotarget. 2017 ; Vol. 8, No. 14. pp. 23213-23227.
@article{e2c6d1ff548b47408a3645d807df4d41,
title = "PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines",
abstract = "B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110α BYL719 inhibitor and the dual p110γ/p110δ inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.",
keywords = "Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Benzamides, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Drug Synergism, Fusion Proteins, bcr-abl, Humans, Imatinib Mesylate, Isoenzymes, Isoquinolines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyrimidines, Thiazoles, Triazines, Journal Article",
author = "Simona Ultimo and Carolina Simioni and Martelli, {Alberto M} and Giorgio Zauli and Camilla Evangelisti and Claudio Celeghini and McCubrey, {James A} and Giorgia Marisi and Paola Ulivi and Silvano Capitani and Neri, {Luca M}",
year = "2017",
month = "4",
day = "4",
doi = "10.18632/oncotarget.15542",
language = "English",
volume = "8",
pages = "23213--23227",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "14",

}

TY - JOUR

T1 - PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines

AU - Ultimo, Simona

AU - Simioni, Carolina

AU - Martelli, Alberto M

AU - Zauli, Giorgio

AU - Evangelisti, Camilla

AU - Celeghini, Claudio

AU - McCubrey, James A

AU - Marisi, Giorgia

AU - Ulivi, Paola

AU - Capitani, Silvano

AU - Neri, Luca M

PY - 2017/4/4

Y1 - 2017/4/4

N2 - B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110α BYL719 inhibitor and the dual p110γ/p110δ inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.

AB - B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110α BYL719 inhibitor and the dual p110γ/p110δ inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Apoptosis

KW - Benzamides

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Drug Resistance, Neoplasm

KW - Drug Synergism

KW - Fusion Proteins, bcr-abl

KW - Humans

KW - Imatinib Mesylate

KW - Isoenzymes

KW - Isoquinolines

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive

KW - Phosphatidylinositol 3-Kinases

KW - Protein Kinase Inhibitors

KW - Purines

KW - Pyrazoles

KW - Pyrimidines

KW - Thiazoles

KW - Triazines

KW - Journal Article

U2 - 10.18632/oncotarget.15542

DO - 10.18632/oncotarget.15542

M3 - Article

VL - 8

SP - 23213

EP - 23227

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 14

ER -