Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma

Abstract

Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma.

DA7R: A 7-Letter Zip Code to Target PDAC

“…The former is based on peptide DA7R, expected to target the NRP-1/VEGFR2 receptor complex in PDAC cells, as it does in other systems. As payload, i.e., chemotherapeutic active principle, we used PAPTP, a mitochondriotropic drug under development in our group [ 44 , 45 , 46 , 50 , 51 , 52 ].…”

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…The researchers found that the Kv1.3 inhibitor tetrahydropyran inhibited PC cell proliferation and induced apoptosis ( 58 ). In vitro experiments revealed that the mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP were able to promote apoptosis in multiple myeloma cell lines L-363 and RPMI-8226 ( 67 ). Mitochondrial targeting inhibitors have been found to alter mitochondrial function by inhibiting Kv1.3 leading to reactive oxygen species mediated apoptosis of cancer cells in vivo in vitro and in vivo experiments in melanoma and pancreatic ductal adenocarcinoma (PDAC) ( 68 ).…”

Structure of the voltage-gated potassium channel K V 1.3: Insights into the inactivated conformation and binding to therapeutic leads

“…K V 1.3 is also recognized as a therapeutic target to modulate the function of autoreactive B cells in granulomatosis with polyangiitis [ 32 ], disease-associated microglia in Alzheimer’s disease, Parkinson’s disease and ischemic stroke [ 37–45 ], macrophages [ 46 ] and neutrophils [ 22 ] in autoimmune and neuroinflammatory diseases [ 23 ]. In addition, mitochondrial K V 1.3 is recognized as a target for the treatment of diverse tumors [ 47 , 48 ]. Since K V 1.3-knockout mice and rats do not exhibit a deleterious phenotype, selective pharmacological targeting of K V 1.3 should be safe [ 27 , 49–51 ].…”