Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cells

Abstract

BackgroundDespite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies.MethodsAn in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria.FindingsWe identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition.InterpretationDual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development.FundThis work was funded by the (RMR), (RMR), the (RMR), the (RMR), (RMR), and (IJC).

Histamine receptor 1 is expressed in leukaemic cells and affects differentiation sensitivity

“…Then, the lower levels of HRH1 observed in AML and MDS could be related to the low levels of HRH1 seen in HSCs and non‐myeloid blood cells, as previously reported (Figure 1A). 2 On the other hand, pharmacological modulation or CRISPR‐mediated KD of HRH1 did not induce significant effects on chemosensitivity or basal differentiation state, while histamine induced only a moderate reduction in clonogenic capacity, thus precluding the therapeutic potential of HRH1 targeting in myeloid malignancies and further supporting a minor role of HRH1, in line with previous results 5 . Despite the lack of effects of HRH1 modulation in leukaemogenesis, our results establish a role for HRH1 in myeloid differentiation.…”

“…Histamine is a pleiotropic biogenic amine acting through four different histamine receptors (HRH1 to HRH4) belonging to the G protein‐coupled receptor superfamily. Although most of the proposed effects of histamine on myeloid differentiation are mediated by HRH2, 2,3 the expression of HRH1 in AML cell lines has recently been reported 5 . Nevertheless, no role for HRH1 in leukaemia has been identified.…”

“…Given this HRH1 expression pattern in AML, we next interrogated the role of HRH1 signalling on cellular viability and clonogenic capacity both in primary AML samples and healthy donor cells. As we have previously described cytotoxic effects of several antihistamines based on their physicochemical properties and independently of HRH1, 5 we selected fexofenadine and cetirizine, potent HRH1 antagonists devoid of these properties. In all healthy samples, agonism or antagonism of HRH1 produced no significant effects on the clonogenicity, while on neoplasic ones only histamine caused a slight reduction (Figure 1B,C).…”

Role of Mitochondria in Cancer Stem Cell Resistance

“…Cationic amphiphilic drugs (CAD), including loratadine and ebastine, can exert their effect through accumulation in both mitochondria and lysosomes [ 214 ]. However, the inhibition of autophagy/mitophagy in certain steps produces increased drug sensitivity.…”

The emergence of antihistamines as unexpected allies in our fight against acute myeloid leukaemia

“…Using an in silico screening assay to assess the cytotoxic effects of FDA-approved drugs for the treatment of AML, Cornet-Masana and colleagues [3] identified a subset of antihistamines with distinct physicochemical properties that selectively killed AML cell lines and primary patient samples. Starting with gene expression profiling experiments involving an MLL-AF9 induced AML model, the authors found HRH1 inverse agonists had properties that reversed the transformation gene signature.…”