Macrolide Antibiotics By Modulating the Autophagic Flux Exert an Antileukemic Effect through the Involvement of hERG1 Potassium Channel

Macrolide Antibiotics (MAs) have been recently shown to exert an antineoplastic activity in different types of cancers, including hematologic malignancies alone or in combination with either chemotherapeutic drugs or tyrosine kinase inhibitors. How MAs can exert an antineoplastic activity is still under investigation and different mechanisms have been proposed, such as inhibition of late phase autophagy, induction of apoptosis, inhibition of tumor-induced angiogenesis, reactive oxygen species production, reduction of mitochondrial biogenesis and inhibition of P-glycoprotein (PgP). MAs are also known to block cardiac hERG1 currents and for this reason can cause QT prolongation. Among MAs antibiotics, erythromycin (Er) and clarithromycin (Cla) have no particularly harmful side effects, have a low risk of TdP and in fact are in clinical use by many years. In addition, it was recently reported that the concomitant administration of Er may provide a reduction in cardiac liability of potent hERG1-blocking drugs due to the occupancy by Er of the external site that reduces the affinity of hERG1 blockers for their specific binding site inside the pore region of the channel. We have provided several evidences that hERG1 channels are often aberrantly expressed in human cancers including leukemias and two conductive isoforms of the channel have been identified so far, hERG1A and hERG1B, the latter prevailing in leukemias. hERG1 blockade exerts an antileukemic effect in vitro and in vivo in preclinical models. In acute myeloid leukemias (AML), hERG1 mediates the FLT-1-dependent cell migration and invasion hence conferring a greater malignancy, while in acute lymphoblastic leukemia (ALL), hERG1 channels modulate pro-survival signals triggered by bone marrow stromal cells (MSC) in the bone marrow microenvironment and the block of hERG1 activity overcomes chemoresistance. MAs are also known to inhibit hERG1 currents, which, conversely, are emerging as regulators of leukemia cell survival and chemoresistance. We analyzed the role of hERG1 on the MAs-induced effects on AL, providing evidence that (1) both hERG1 blockade and silencing modulate autophagy, triggering autophagic and apoptotic cell death, similarly to MAs; (2) MAs block hERG1-sustained currents in AL and (3) the effects of MAs depend on hERG1 inhibition. We tested the activity of a panel of MAs on acute leukemias (AL), both myeloid and lymphoid, alone and in combination with chemotherapeutic agents commonly used for AL treatment. MA's effects were tested both in vitro and in preclinical mouse models. We provide evidence that MAs in AL (1) have an antileukemic effect; (2) modulate autophagy, triggering it and then blocking the autophagic flux; (3) affect intracellular signaling pathways, in turn leading to both apoptotic and autophagic cell death. Overall we propose to include MAs in the treatment schedule of ALs, especially for chemoresistant forms.