Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the μM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of tumors, being the fourth leading cause of cancer mortality
In light of the results obtained with clofazimine on B-CLL cells and in the orthotopic melanoma model, and of indications of expression of Kv1.3 in pancreatic cancer tissues, we investigated whether this drug can be used against PDAC in an orthotopic xenograft model
Since our purpose was to understand whether clofazimine might be useful to induce apoptosis in PDAC cell lines via inhibition of the mitochondrial Kv1.3 channel, first we checked whether some of the widely used human PDAC lines of various origin express Kv1.3
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of tumors, being the fourth leading cause of cancer mortality. Patients are diagnosed at a rather late stage of disease and their life expectancy is at most five years after diagnosis. The only valid therapeutic approach is the radical surgical resection of the tumor, which is feasible only in 20% of the cases, and recurrence of cancer lesions often occurs. Some other patients (30-40%) show unresectable locally advanced pancreatic cancer (LAPC) with a median survival of one year [1]. For the rest of the patients, who manifest metastasis at diagnosis, six months is the expected survival period For about 20 years, the only therapeutic option considered valid for the treatment of PDAC has been 5-fluorouracil (5-FU). The mechanism of action by which the cytotoxic effect is exerted by these molecules is the block of DNA synthesis; considerable side effects occur in the healthy tissues
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