Abstract
BackgroundPancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment.MethodsThe effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay.ResultsWhen used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines.ConclusionsThis study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.
Highlights
IntroductionCombination therapies with classical chemotherapeutic agents improved treatment of advanced Pancreatic cancer (PC) at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%
Pancreatic cancer (PC) is the fourth most common cause of cancer death
Nelfinavir and nitroxoline affect cell cycle in PC cell lines To investigate whether the decreased PC cell viability observed in response to erlotinib, nelfinavir and nitroxoline could be due to decreased proliferation, we first evaluated cell cycle distribution by flow cytometry (Fig. 2)
Summary
Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Combination chemotherapies using gemcitabine plus albumin-bound paclitaxel (nab-paclitaxel) or FOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin) are more effective than single chemotherapeutic agents providing a clear improvement in the treatment of PC patients with good performance status [2]. Each of these agents has a relevant toxicity that becomes even more marked when they are used in combination [1]. There is an urgent need to find more effective and less toxic therapeutic approaches to treat this lethal disease
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