Pancreas ductal
adenocarcinoma (PDAC) is one the most aggressive
cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial
voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all
tumors expressed Kv1.3 with 60% of
tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas
tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in
tumor reductions of 87% and 70%, respectively. When combined with clinically used
Gemcitabine plus
Abraxane (
albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated
tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the
antioxidant system. In contrast,
tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic
chemotherapies might be a novel, effective treatment for PDAC.