Eliminazione delle cellule del cancro al seno tramite modulazione dei canali del potassio.

PHARMACOLOGICAL MODULATION OF THE MITOCHONDRIAL POTASSIUM CHANNEL KV1.3 TRIGGERS APOPTOSIS OF CANCER STEM CELLS AND PREVENTS MAMMOSPHERE FORMATION Triple Negative Breast Cancer (TNBC) is a heterogenous, recurring cancer with a high rate of metastasis, poor prognosis and lack of therapeutic targets. Various murine and human TNBC cells express high level of the mitochondrial Kv1.3 ion channel. Therefore, we investigated the effects of Kv1.3 inhibitors that are either membrane-impermeant and act on the plasma membrane-located channels, or two inhibitors that act on the mitochondria-located channel. These latter inhibitors, PAPTP and PCARBTP, were able to trigger apoptosis in 2D TNBC cultures by altering the mitochondrial function and leading to reactive oxygen species release. Gemcitabine acted synergistically with PAPTP and PCARBTP. These modulators at sublethal doses were very efficient in 3D mammosphere models, developed with both murine and mammalian TNBC cells as well, while membrane-impermeant toxin inhibitors of Kv1.3 were without effect. The efficiency of PAPTP and PCARTP to inhibit mammosphere formation was increased in combination treatment with gemcitabine. The combination treatment abolished CSC population in the mammospheres, as confirmed by advanced Aldefluor assay. Further biochemical experiments highlighted that PAPTP in combination with gemcitabine affected cellular pathways that are crucial for cancer stemness potential. Overall, our results show that mitochondrial Kv1.3 inhibitors along with gemcitabine are promising agents against TNBC as they efficiently impair mammosphere formation.