Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.
Highlights
Pancreatic adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor prognosis and low life expectancy
We focus our attention on determining the mechanisms of action of the repositioned drug TFP, which induced cell death in PDAC, to rationally propose a possible combination of TFP with drugs used in clinical settings
Repurposing them as combinatory therapy may lead to developing new treatments for pancreatic adenocarcinoma
Summary
Pancreatic adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor prognosis and low life expectancy. Present and future research should be focused on improving PDAC therapies to find effective treatments. The repurposing of approved drugs to treat cancer has become an attractive strategy. This approach uses compounds with a known risk, which allows faster access of patients to drugs and lower development costs. This was the case of drugs like celecoxib, metformin or sulindac, which went through clinical trials [2]. Many other compounds can be Cancers 2019, 11, 1869; doi:10.3390/cancers11121869 www.mdpi.com/journal/cancers
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