Abstract
BackgroundIon channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation.MethodsHere we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 genetic CLL murine model, characterized by a lympho-proliferative disease reminiscent of aggressive human CLL. Eμ-TCL1 mice showing overt disease state were treated with intraperitoneal injections of non-toxic 5 nmol/g PAPTP or 10 nmol/g TRAM-34 once a day and the number and percentage of pathological B cells (CD19+CD5+) in different, pathologically relevant body districts were determined.ResultsWe show that Kv1.3 expression correlates with sensitivity of the human and mouse neoplastic cells to PAPTP. Primary CLL cells from ibrutinib-resistant patients could be killed with PAPTP and this drug enhanced the effect of Venetoclax, by acting on mitoKv1.3 of the inner mitochondrial membrane and triggering rapid mitochondrial changes and cytochrome c release. In vivo, after 2 week- therapy of Eμ-TCL1 mice harboring distinct CLL clones, leukemia burden was reduced by more than 85%: the number and percentage of CLL B cells fall in the spleen and peritoneal cavity and in the peripheral blood, without signs of toxicity. Notably, CLL infiltration into liver and spleen and splenomegaly were also drastically reduced upon PAPTP treatment. In contrast, TRAM-34 did not exert any beneficial effect when administered in vivo to Eμ-TCL1 mice at non-toxic concentration.ConclusionAltogether, by comparing vehicle versus compound effect in different Eμ-TCL1 animals bearing unique clones similarly to CLL patients, we conclude that PAPTP significantly reduced leukemia burden in CLL-relevant districts, even in animals with advanced stage of the disease. Our results thus identify PAPTP as a very promising drug for CLL treatment, even for the chemoresistant forms of the disease.
Highlights
Ion channels are emerging as promising oncological targets
Altogether, by comparing vehicle versus compound effect in different Eμ-T cell leukemia/lymphoma 1A (TCL1) animals bearing unique clones to chronic lymphocytic leukemia (CLL) patients, we conclude that PAPTP significantly reduced leukemia burden in CLL-relevant districts, even in animals with advanced stage of the disease
We show that Kv1.3 expression in human primary CLL B cells correlates with sensitivity of the neoplastic cells to the mitochondria-targeted inhibitor PAPTP (1 μM) that acts on the mitochondrial counterpart of Kv1.3 (Fig. 1a)
Summary
Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. The B-cell chronic lymphocytic leukemia (CLL) has high incidence among adults in the Western countries, being the most frequent type of leukemia This clinically heterogeneous disease is characterized by a relatively homogeneous transcriptional profile and immunophenotype, and by an aberrant accumulation of mature, apoptosis-resistant CD19+CD5+ monoclonal B-lymphocytes in peripheral blood [1]. Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), a key player in B-cell receptor (BCR) signaling that regulates B-cell growth. This drug is effective against aggressive forms of CLL with mutations of the tumor suppressor TP53 [3], whose activation is required to trigger the intrinsic apoptotic pathway. Novel therapeutic strategies and approaches for drug discovery and development are nowadays unmet clinical needs
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