Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Abstract

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

Pulmonary Hypertension: New Insights and Recent Advances from Basic Science to Translational Approaches

“…The administration of TFP in two experimental rat models (Monocrotaline-and Sugen/hypoxia-induced PAH) significantly lowered RVSP, diminished total pulmonary resistance, decreased the medial wall thickness of distal pulmonary arteries, and improved RV function. Overall, these data indicate that TFP might provide beneficial effects for the treatment of PAH and support the notion that finding new applications for old medications could be a very productive approach [7].…”

The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure

“…28 In addition, in support of the prevailing model of PAH development, that is, initial apoptosis of PA endothelial cells followed by extensive proliferation of adjacent PA smooth muscle cells (PASMCs) and apoptosis-resistant PA endothelial cells, 29 the development of the rat Su/ hypoxic (Su/Hx) model represents a significant advance providing a complementary alternative to the MCT rat model. Indeed, due to its ability to cause severe and irreversible PH with the appearance of angio-obliterative lesions, the Su/Hx rat model (while certainly not without criticism) has become one of the most used preclinical models of PAH with therapeutic intervention initiated at either 3 weeks (immediately after the end of hypoxia exposure) or 5 to 8 weeks (after 2-5 weeks of normoxic recovery) post-Su injection 26,[30][31][32] (Figure 1). More recently, the rat Su/Hx model was adapted to mice 33 to take benefit of existing genetically modified mice and thus gain mechanistic insights into the pathogenesis of PAH.…”

The role of phenothiazine derivatives in autophagy regulation: A systematic review

“…Moreover, the authors observed a dose‐dependent increase in LC3‐II level, which indicates autophagosome accumulation. An immunofluorescence analysis confirmed the accumulation of cytoplasmic LC3‐positive dots after trifluoperazine treatment (Grobs et al, 2021).…”

“…The impact of trifluoperazine (5 and 10 μM) on autophagy of pulmonary artery smooth muscle cells with pulmonary arterial hypertension (PAH‐PASMCs) cells was analyzed by Grobs et al (2021). The bright‐field phase‐contrast microscope analysis showed an accumulation of small and large vesicle‐like structures, which is a feature typically observed in autophagy.…”

“…Breast: breast cancer MDA-MB-231 (Indelicato et al, 2010, Tafani et al, 2008 induction: "LC3-II (Indelicato et al, 2010, Tafani et al, 2008; # p62 (Indelicato et al, 2010) Colon: colon cancer HCT116 (Qian et al, 2019) suppression: "LC3and p62 (Qian et al, 2019) Hematopoietic system: multiple myeloma cell lines U-266 and RPMI8226 (Li, Chen, et al, 2020) suppression: " LC3-I, p62; # LC3-II (Li, Chen, et al, 2020) Lungs: lung cancer A549, H69, H82, H125, H157, H592, U-1285, U-1810 (Zong et al, 2014), pulmonary artery smooth muscle cells with pulmonary arterial hypertension (Grobs et al, 2021) induction: "LC3-II (Zong et al, 2014), small and large vesicle-like structures (Grobs et al, 2021), no impact on p62 (Zong et al, 2014) Sex organs: cervical cancer HeLa (Conway et al, 2013) induction: "LC3-II (Conway et al, 2013) Skin: melanoma cell lines B16, A375, W266-4, A875, HT144, SK-MEL-2, and WM115 (Xia, Xu, et al, 2021) suppression: "LC3-II and p62, LC3 puncta (Xia, Xu, et al, 2021) Novel phenothiazine derivative (DS00329)…”