Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival

Kosić, Marija; Nesic, Zorica; Glumac, Sofija; Vasić, Marko; Pajović, Vladislav; Savić, Bojana; Japundžić‐Žigon, Nina

doi:10.1016/j.biopha.2021.112411

Cited by 5 publications

(5 citation statements)

References 42 publications

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“…Furthermore, combination treatment with PX and DOX has been demonstrated to yield inhibitory effects on TNBC at lower dosages, mitigating the long-term cardiac effects associated with high-dose DOX administration. Kosić et al have highlighted the cardioprotective potential of DOX–PX synergy, which is characterized by reduced DOX-induced cardiotoxicity and improved survival rates, providing a grounded rationale for their conjoined deployment in mitigating the side effects of DOX [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux

Huang,

Wu,

et al. 2024

Cancers

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The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.

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Section: Discussionmentioning

confidence: 99%

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux

Huang,

Wu,

et al. 2024

Cancers

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“…In conclusion, our study highlights the key role of GRK2 in the progression of cardiac remodeling. Notably, several studies have demonstrated the protective effect of paroxetine as a GRK2 inhibitor in cardiovascular diseases [23,25,28]. The transcription factor NF-κB has a key role in cardiac remodeling pathology [58].…”

Section: Discussionmentioning

confidence: 99%

“…Forward Reverse Primer sequences used for real-time PCR [23,48,[52][53][54][55][56][57]. GRK2, G protein-coupled receptor kinase 2; NFκB, Nuclear factor-kappa-light-chain-enhancer of activated B-cells; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; α-SMA, alpha-smooth muscle actin; ANP, Atrial natriuretic peptide; TGF-β1, Transforming growth factor beta 1; Smad3, Mothers against decapentaplegic homolog 3; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase.…”

Section: Genementioning

confidence: 99%

“…Paroxetine, a selective serotonin reuptake inhibitor (SSRI) with ATC code (N06AB), is an FDA-approved drug for the treatment of depression [22]. Paroxetine has been shown to have a selective and potent inhibitory effect on GRK2 activity by specifically binding to its catalytic domain [23][24][25]. Kowalska et al (2021) reported that paroxetine has a promising therapeutic effect as it is able to interact with numerous molecular targets [22].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown the potential of paroxetine as a GRK2 inhibitor to reverse cardiac remodeling in experimental models of acute myocardial infarction [23,28,29]. This kinase inhibitory function influences myocyte contractility.…”

Section: Introductionmentioning

confidence: 99%

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Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression

Alonazi,

Bin Dayel,

Albuaijan

et al. 2023

IJMS

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Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.

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Boesenbergia rotunda displayed anti-inflammatory, antioxidant and anti-apoptotic efficacy in doxorubicin‐induced cardiotoxicity in rats

Zhang

Jiang

Wang

et al. 2023

Sci Rep

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This study evaluated the cardioprotective properties of Boesenbergia rotunda extract (BrE) against doxorubicin (DOX) induced cardiotoxicity. Rats received oral gavage of BrE for 28 days and DOX (5 mg/kg/week for 3 weeks). Thereafter the animals were sacrificed, blood and cardiac samples were collected for biochemical, histological and immunohistochemical analyses. The results indicated that BrE attenuated DOX triggered body and cardiac weight loss and prevented against cardiac injury by mitigating histopathological alterations in cardiac tissues as well as serum cardiac function enzymes. BrE significantly reduced serum levels of aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), troponin T (TnT) and creatine kinase-MB (CK-MB) in DOX-treated rats. Furthermore, BrE alleviated cardiotoxicity by reducing DOX instigated oxidative stress and potentiating the level of glutathione, as well as the activities superoxide dismutase and catalase in cardiac tissues. In addition, BrE significantly decreased the characteristic indices of DOX-induced cardiac inflammation and apoptosis. Immuno-histochemical analysis revealed that BrE decreased the stain intensity of p53 and myeloperoxidase (MPO) proteins compared to the DXB alone group. In conclusion, our results indicated that BrE modulated oxidative stress, inflammation and apoptosis to attenuate DOX-induced cardiac damage.

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Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival

Cited by 5 publications

References 42 publications

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux

Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression

Boesenbergia rotunda displayed anti-inflammatory, antioxidant and anti-apoptotic efficacy in doxorubicin‐induced cardiotoxicity in rats

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