The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

Isabella Spinello, Ernestina Saulle, Maria Teresa Quaranta, Luca Pasquini, Elvira Pelosi, Germana Castelli, Tiziana Ottone, Maria Teresa Voso, Ugo Testa, Catherine Labbaye

Research output: Contribution to journalArticle

Abstract

CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematological target and whether its inhibitor AC-73 may be used in leukemia therapy, may reveal an alternative treatment strategy in patients with acute myeloid leukemia. We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with acute myeloid leukemia. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. In our study, we demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy, by enhancing leukemic cells sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of acute myeloid leukemia and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.

Original languageEnglish
JournalHaematologica
DOIs
Publication statusE-pub ahead of print - Nov 22 2018

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Autophagy
Myeloid Cells
Acute Myeloid Leukemia
Cytarabine
Cell Proliferation
Leukemia
Neoplasms
Hematopoietic Stem Cells
Fetal Blood
Pharmaceutical Preparations
Glycoproteins
Stem Cells
Therapeutics
Drug Therapy
Cell Line
Growth
arsenic trioxide

Cite this

@article{144098c78b6046b6a006ad9e82ccfe7f,
title = "The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells",
abstract = "CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematological target and whether its inhibitor AC-73 may be used in leukemia therapy, may reveal an alternative treatment strategy in patients with acute myeloid leukemia. We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with acute myeloid leukemia. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. In our study, we demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy, by enhancing leukemic cells sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of acute myeloid leukemia and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.",
author = "Isabella Spinello and Ernestina Saulle and Quaranta, {Maria Teresa} and Luca Pasquini and Elvira Pelosi and Germana Castelli and Tiziana Ottone and Voso, {Maria Teresa} and Ugo Testa and Catherine Labbaye",
note = "Copyright {\circledC} 2018, Ferrata Storti Foundation.",
year = "2018",
month = "11",
day = "22",
doi = "10.3324/haematol.2018.199661",
language = "English",
journal = "Haematologica",
issn = "0390-6078",
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TY - JOUR

T1 - The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

AU - Spinello, Isabella

AU - Saulle, Ernestina

AU - Quaranta, Maria Teresa

AU - Pasquini, Luca

AU - Pelosi, Elvira

AU - Castelli, Germana

AU - Ottone, Tiziana

AU - Voso, Maria Teresa

AU - Testa, Ugo

AU - Labbaye, Catherine

N1 - Copyright © 2018, Ferrata Storti Foundation.

PY - 2018/11/22

Y1 - 2018/11/22

N2 - CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematological target and whether its inhibitor AC-73 may be used in leukemia therapy, may reveal an alternative treatment strategy in patients with acute myeloid leukemia. We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with acute myeloid leukemia. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. In our study, we demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy, by enhancing leukemic cells sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of acute myeloid leukemia and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.

AB - CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematological target and whether its inhibitor AC-73 may be used in leukemia therapy, may reveal an alternative treatment strategy in patients with acute myeloid leukemia. We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with acute myeloid leukemia. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. In our study, we demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy, by enhancing leukemic cells sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of acute myeloid leukemia and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.

U2 - 10.3324/haematol.2018.199661

DO - 10.3324/haematol.2018.199661

M3 - Article

C2 - 30467201

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -