Paroxetine Hydrochloride

Germann, David; George, M. Anne; Han, Feixue; Tikhomirova, Anna

doi:10.1016/b978-0-12-407691-4.00008-3

Cited by 15 publications

(8 citation statements)

References 53 publications

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“…We performed a preliminary screening of many small molecules provided by Gu et al (2013) and discovered that Paxil exhibited considerable cancer suppressive capacity accompanied by its functions as an autophagy inhibitor. Paroxetine hydrochloride (Paxil), a phenylpiperidine derivative, is a selective serotonin reuptake inhibitor prescribed to treat mood disorders (e.g., depression, generalized anxiety disorders, and obsessive-compulsive disorder) (Germann et al, 2013). Based on the excellent medicinal characteristics of Paxil, in the present study, we sought to evaluate its anti-cancer activity both in vitro and in vivo, and further elucidate the associated underlying mechanisms in lung cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

Wang

Gong

Zhan

et al. 2020

Front. Cell Dev. Biol.

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Cancer cells are characterized by malignant proliferation and aberrant metabolism and are thereby liable to the depletion of nutrients and accumulation of metabolic waste. To maintain cellular homeostasis, cancer cells are prone to upregulating the canonical autophagy pathway. Here, we identified paroxetine hydrochloride (Paxil) as a late autophagy inhibitor and investigated its killing effect on lung cancer cells and with a xenograft mouse model in vivo. Upregulated LC3-II and p62 expression indicated that Paxil inhibited autophagy. Acid-sensitive dyes (e.g., LysoTracker and AO staining) indicated reduced lysosomal acidity following Paxil treatment; consequently, the maturation of the pH-dependent hydroxylases (e.g., cathepsin B and D) substantially declined. Paxil also induced the fragmentation of mitochondria and further intensified ROS overproduction. Since the autophagy pathway was blocked, ROS rapidly accumulated, which activated JNK and p38 kinase. Such activity promoted the localization of Bax, which led to increased mitochondrial outer membrane permeability. The release of Cytochrome c with the loss of the membrane potential triggered a caspase cascade, ultimately leading to apoptosis. In contrast, the clearance of ROS by its scavenger, NAC, rescued Paxil-induced apoptosis accompanied by reduced p38 and JNK activation. Thus, Paxil blocked the autophagic flux and induced the mitochondria-dependent apoptosis via the ROS-MAPK pathway.

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Section: Introductionmentioning

confidence: 99%

Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

Wang

Gong

Zhan

et al. 2020

Front. Cell Dev. Biol.

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“…In many countries, selective serotonin reuptake inhibitors are the preferred antidepressant drug[17] because they are generally well tolerated, have a low discontinuation rate[18], and are simple to administer, which reduces the risk of inadequate doses in depressed patients. We adopted the selective serotonin reuptake inhibitor paroxetine (Seroxat) as the basic medicationin the present study because it has a strong effect on severe depression, obsessive-compulsive disorder, panic, generalized anxiety, social phobia and post-traumatic stress disorder; it also exhibits strong sedative effects[19]. …”

Section: Discussionmentioning

confidence: 99%

Acupuncture/electroacupuncture enhances anti-depressant effect of Seroxat: the Symptom Checklist-90 scores

Chen

Lin²,

Wang

et al. 2014

Neural Regen Res

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One hundred and five patients with primary unipolar depression were randomly divided into three groups: drug group (Seroxat administration), acupuncture group (Seroxat plus acupuncture), and electroacupuncture group (Seroxat plus acupuncture plus electroacupuncture). Patients’ symptoms were evaluated using a psychometric questionnaire, the Symptom Checklist-90, before intervention and after 2, 4, 6 and 10 weeks of treatment. The individual factor scores and the total score from the Symptom Checklist-90 reduced in all three groups as treatment progressed. In the acupuncture and electroacupuncture groups, the total score and the factor scores for obsessive-compulsive symptoms, depression, and anxiety were significantly lower than those in the drug group. There was no significant difference in the factor scores or total scores between the acupuncture and electroacupuncture groups. Some factor scores in the electroacupuncture group, such as somatization, depression, hostility, and phobic anxiety, were increased at 10 weeks compared with the respective score immediately after the course of electroacupuncture at 6 weeks. Our findings indicate that administration of Seroxat alone or in combination with acupuncture/electroacupuncture can produce a significant effect in patients with primary unipolar depression. Furthermore, acupuncture/electroacupuncture has a rapid onset of therapeutic effect and produces a noticeable improvement in obsessive-compulsive, depressive and anxiety symptoms.

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“…We selected a high concentration of 15 mmol/L, preserving at least 50% viable cells, and a low concentration of 2 mmol/L, high enough to inhibit GRK2 yet with negligible effects on cell viability at 24 hours, to verify the molecular mechanism in subsequent experiments. The low dose is also clinically relevant as toxicological tests demonstrate acceptable plasma concentrations of PX up to 3 mmol/L (43,44). We investigated the consequences of PX treatment on IGF1R downregulation, signaling, and overall cell survival, alongside their dependency on b-arr1.…”

Section: Pharmacologic Inhibition Of Grk2 Downregulates Igf1r Through a B-arr1-dependent Mechanismmentioning

confidence: 99%

Inhibition of G Protein–Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth

et al. 2021

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The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G proteincoupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancerrelevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapymediated removal from the cell surface activates cancer-protective b-arrestin-biased signaling (b-arr-BS). As these overlapping processes are initiated by the b-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and b-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced b-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose-and timedependent IGF1R downregulation without associated b-arr-BS.In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between b-arrestin isoforms; in low ligand conditions, PX favored b-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK.Significance: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1Rtargeted therapy in cancer.

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Paroxetine Hydrochloride

Cited by 15 publications

References 53 publications

Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

Acupuncture/electroacupuncture enhances anti-depressant effect of Seroxat: the Symptom Checklist-90 scores

Inhibition of G Protein–Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth

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