Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

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.

NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response

“…NUPR1 is stress‐activated protein rapidly expressed in response to acute stress events including sepsis and pancreatitis 17,30‐33 . Recent studies suggest NUPR1 affects the ER stress response 16,34 contributing to hepatocarcinogenesis 17 . Since NUPR1 has been linked to oxidative stress and is required for a proper UPR activation under acute stress conditions, we wanted to examine NUPR1's role in a more clinically relevant form of liver damage.…”

Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma

“…In addition, proteasome inhibition by bortezomib, an approved first-line drug for MM, was shown to increase pancreatic cancer cell sensitivity to TFP [15].…”

“…In addition, proteasome inhibition by bortezomib, an approved first‐line drug for MM, was shown to increase pancreatic cancer cell sensitivity to TFP [15]. In subsequent experiments, further study should be conducted to determine the association between TFP and bortezomib in MM.…”

“…Considering that TFP plays an inhibitory role in various tumors [5,15], we treated MM cells with different concentrations of TFP (0, 5, 10, 20, 30, 40 lm) to investigate the role of TFP in MM. After treatment for 24 h, we performed the CCK-8 assay to evaluate the cell viability.…”

Mitophagy in Pancreatic Cancer

“…Regulated cell death further includes apoptotic and non-apoptotic forms. In addition to the extensively studied apoptosis (91,92), the induction of nonapoptotic regulated cell death [such as necroptosis (93,94), alkaliptosis (95,96), and ferroptosis (97)(98)(99)(100)(101)] in preclinical PDAC models has shown promising results in inhibiting tumor growth. As a metabolic center, mitochondria play a complex role in regulating apoptosis and non-apoptotic cell death by cooperating with other subcellular organelles (102).…”