Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo

Abstract

The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

“…Importantly, clofazimine and the recently developed mitochondria-targeted inhibitors of Kv1.3 PAPTP and PCARBTP showed more than 90% tumor reduction in an in vivo B16F10 mouse melanoma model [13,14] without causing obvious side-effects. Kv1.3 channel blockers were further used ex vivo in primary B cells from chronic lymphocytic leukemia (B-CLL) patients [12,13]. Characterized by a higher level of functional Kv1.3 channel compared to non-malignant B and T cells of the same patient or of healthy subjects, patients' B-CLL cells underwent cell death after inhibition of Kv1.3, whereas non-malignant lymphocytes, expressing less Kv1.3, were spared [12,13].…”

“…These Kv1.3 inhibitors were shown to induce the intrinsic apoptotic pathway in multiple human and murine mitoKv1.3-expressing cells including Jurkat T lymphoma, osteosarcoma SAOS-2, B16F10 melanoma cells as well as human pancreas cancer cells and B-lymphocyte chronic leukemia cells, whereas cells displaying a low or no Kv1.3 current, such as K562, or human primary skin fibroblasts did not undergo apoptosis when treated with these inhibitors [13,14]. Importantly, clofazimine and the recently developed mitochondria-targeted inhibitors of Kv1.3 PAPTP and PCARBTP showed more than 90% tumor reduction in an in vivo B16F10 mouse melanoma model [13,14] without causing obvious side-effects. Kv1.3 channel blockers were further used ex vivo in primary B cells from chronic lymphocytic leukemia (B-CLL) patients [12,13].…”

“…Kv1.3 channel blockers were further used ex vivo in primary B cells from chronic lymphocytic leukemia (B-CLL) patients [12,13]. Characterized by a higher level of functional Kv1.3 channel compared to non-malignant B and T cells of the same patient or of healthy subjects, patients' B-CLL cells underwent cell death after inhibition of Kv1.3, whereas non-malignant lymphocytes, expressing less Kv1.3, were spared [12,13].…”

“…Since then, specific membrane permeant inhibitors, including the Ruta graveolens plant derived psoralens Psora-4, and PAP-1, the anti-mycobacterial drug clofazimine and novel mitochondrial targeted PAP-1 derivatives, namely PAPTP and PCARBTP, synthesized by our group, were used to mimic the interactions of Bax and mitoKv1.3 in different cancer cell lines that express Kv1.3 [12,13]. These Kv1.3 inhibitors were shown to induce the intrinsic apoptotic pathway in multiple human and murine mitoKv1.3-expressing cells including Jurkat T lymphoma, osteosarcoma SAOS-2, B16F10 melanoma cells as well as human pancreas cancer cells and B-lymphocyte chronic leukemia cells, whereas cells displaying a low or no Kv1.3 current, such as K562, or human primary skin fibroblasts did not undergo apoptosis when treated with these inhibitors [13,14]. Importantly, clofazimine and the recently developed mitochondria-targeted inhibitors of Kv1.3 PAPTP and PCARBTP showed more than 90% tumor reduction in an in vivo B16F10 mouse melanoma model [13,14] without causing obvious side-effects.…”

Kv1.3: a multifunctional channel with many pathological implications

“…While Kv1.3 upregulation in some neoplastic tissues suggests that a selective inhibition may be a therapeutic option, some other types of cancer show decreased expression. Therefore, although direct pharmacological targeting of mitochondrial Kv1.3 effectively eliminates tumor cells [22], indiscriminate Kv1.3 inhibition may not be the best approach, even taking into account that Kv1.3 inhibition would not affect the antitumoral capabilities of the immune system. Additionally, Kv1.3 nonconducting proliferative functions should not be discarded.…”