Acriflavine targets oncogenic STAT5 signaling in myeloid leukemia cells

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.

Repurposing of Acriflavine to Target Chronic Myeloid Leukemia Treatment

“…Furthermore, activating the P21 Waf1 protein, an important marker of cellular senescence, was reported at a low concentration of ACF, suggesting that ACF might also induce a senescent phenotype in CML cells. Finally, ACF showed positive effects in IM-resistant CML cells sensitization, suggesting that ACF might be a useful drug that could be used alone or in combination with IM in order to alleviate resistant cells [75]. In summary, ACF presents a promising therapeutic strategy against CML, by inhibiting both HIF-1 and STAT5 transcription factors, and by eradicating TKI-resistant leukemia cells.…”

“…In 2011, a study showed that ACF inhibited chronic lymphoblastic leukemia (CLL) cell survival and proliferation [52]. Our team recently demonstrated a cytotoxic effect of ACF on MV-4-11 cell line, a current model for acute myeloid leukemia (AML) cells [75]. This is also in agreement with a study by Sabolova et al, who showed that ACF induces a dose-dependent inhibition of proliferation of HL-60 AML cell line and L1210 mice leukemia cells [76].…”

“…In a recent study, our team demonstrated that ACF affected the growth and survival of CML and AML cell lines by targeting the STAT5 and STAT3 signaling pathway, without affecting BCR-ABL expression (Fig. 2) [75]. In fact, STAT3 and STAT5 are two transcription factors that are aberrantly activated in CML models by the constitutive activation of BCR-ABL that phosphorylates STAT factors at their tyrosine residues, causing their excessive activation [91].…”

“…Thus, targeting both HIFs and STAT signaling by ACF might potentially eradicate CML LSCs, and hence, prevent CML patients relapse after TKI treatment. Therefore, ACF-induced downregulation of STAT5 expression/activity in CML, along with the upregulation of STAT3 phosphorylation, could potentially lead to the inhibition of CML cells' survival and proliferation [75]. For instance, the anticancer chemotherapeutic agent doxorubicin showed STAT3 activation through JAK kinase phosphoryla-tion, and was associated with growth inhibition in response to stress generation [98].…”

“…challenge includes the investigation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) of ACF in order to better incorporate it in clinical trials. Regardless of the extensive work required for the study of ACF, its anti-tumor effects have shown to be efficient in different cancers previously mentioned, thus showing promising results in not only eradicating CML, but also in other malignancies and cancer types[52,54,75] …”