Acriflavine targets oncogenic STAT5 signaling in myeloid leukemia cells.

Rawan Hallal,Frédéric Mazurier,Margaux Deynoux,Rawan Nehme,Persio Dello Sbarba,Kazem Zibara,Hassan Dakik,Fabrice Gouilleux,Ali Nehme,Yves Levern,Marie Brachet‐Botineau

doi:10.1111/jcmm.15612

Abstract

Acriflavine (ACF) is an antiseptic with anticancer properties, blocking the growth of solid and haematopoietic tumour cells. Moreover, this compound has been also shown to overcome the resistance of cancer cells to chemotherapeutic agents. ACF has been shown to target hypoxia‐inducible factors (HIFs) activity, which are key effectors of hypoxia‐mediated chemoresistance. In this study, we showed that ACF inhibits the growth and survival of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cell lines in normoxic conditions. We further demonstrated that ACF down‐regulates STAT5 expression in CML and AML cells but activates STAT3 in CML cells in a HIF‐independent manner. In addition, we demonstrated that ACF suppresses the resistance of CML cells to tyrosine kinase inhibitors, such as imatinib. Our data suggest that the dual effect of ACF might be exploited to eradicate de novo or acquired resistance of myeloid leukaemia cells to chemotherapy.

Highlights

Acriflavine (ACF), a mixture of 3,6-diamino-10-methylacridinium chloride and 3,6-diaminoacridine, was first described in 1912 by the Nobel prize Paul Ehrlich as an antiseptic and has been since used to kill parasites
Like in normoxia, ACF reduced STAT5A and STAT5B expression and increased STAT3 phosphorylation (Figure 3E). This indicated that ACF oppositely regulates STAT3 and STAT5 signalling in K562 cells in a hypoxia-inducible factors (HIFs)-independent manner
Identification of key oncogenic drivers has led to the development of drugs that have improved the prognosis of cancer patients

Summary

| INTRODUCTION

Acriflavine (ACF), a mixture of 3,6-diamino-10-methylacridinium chloride (trypaflavine) and 3,6-diaminoacridine (proflavine), was first described in 1912 by the Nobel prize Paul Ehrlich as an antiseptic and has been since used to kill parasites. In the hypoxic bone marrow (BM) microenvironment, HIF-1α has been found to support the persistence of CML leukaemic stem cells (LSCs) in a BCR-ABL kinase–independent manner.[16] HIF-1αinduced metabolic reprogramming is required for imatinib (IM) resistance of CML cells associated with BCR-ABL up-regulation.[17] Cheloni et al have recently shown that ACF inhibits the growth and survival of CML cells as well as the stem cell potential of CML LSCs, while sparing normal haematopoietic stem/progenitor cells They further demonstrated that ACF blocks leukaemia development and reduced CML LSCs maintenance in a CML mouse model.[18] Based on these studies, ACF has been proposed as a new therapeutic approach to prevent the relapse of CML. ACF-mediated modulation of STAT3/5 signalling might be responsible for the antileukaemic activity of this compound

| MATERIAL AND METHODS

Findings

| DISCUSSION