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Acute Myeloid Leukemia
The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells
Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):973-985
Isabella Spinello,1 Ernestina Saulle,1 Maria Teresa Quaranta,1 Luca Pasquini,2 Elvira Pelosi,3 Germana Castelli,3 Tiziana Ottone,4 Maria Teresa Voso,4
Ugo Testa3 and Catherine Labbaye1
1National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome; 2Core Facilities, Istituto Superiore di Sanità; 3Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità and 4Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
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 chemothera- peutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 repre- sents a new hematologic 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 (AML). 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 AML. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. 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-pro- liferative effect additive to chemotherapy by enhancing leukemic cell 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 AML and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeu- tic agents.
Introduction
Targeted therapy for acute myeloid leukemia (AML) represents an ongoing chal- lenge and in this context, cluster of differentiation 147 (CD147) represents an attractive target for therapeutic intervention in AML and in other hematologic neo- plasms.1-3 CD147, also known as basigin or extracellular matrix metalloproteinase inducer (EMMPRIN), is a type-I transmembrane glycoprotein that belongs to the immunoglobulin superfamily. Among the numerous studies that have documented the significance of CD147 in various physiological processes, the best character- ized function of CD147 is related to its role in tumor metastasis, angiogenesis and chemoresistance processes.3-6 Overexpression of CD147 correlates with a number of biological functions that promote tumor progression (e.g. cellular proliferation, angiogenesis, matrix metalloproteinase production) and confers resistance to chemotherapeutic drugs such as adriamycin,7,8 cisplatin.9 CD147 mediates molecu-
Correspondence:
CATHERINE LABBAYE catherine.labbaye@iss.it
Received: June 11, 2018. Accepted: November 15, 2018. Pre-published: November 22, 2018.
doi:10.3324/haematol.2018.199661
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/973
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