Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine

Ghosh, Sayan; Mukherjee, Sudeshna; Choudhury, Sumana; Gupta, P. C. Sen; Adhikary, Arghya; Baral, Rathindranath; Chattopadhyay, Sreya

doi:10.1016/j.cellsig.2015.03.013

Cited by 56 publications

(55 citation statements)

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“…Increased expression of pro‐apoptotic proteins such as Bax and cleaved caspase‐3 was detected in the LPS+ Fluoxetine group as compared to the LPS group and a simultaneous decrease in the anti‐apoptotic protein Bcl2 (Figure a). These changes were in accordance with previously described observations . These apoptotic changes were further evidenced by increased nuclear fragmentation in the thymocytes obtained from the fluoxetine‐supplemented LPS group as compared to the LPS‐only group (Figure b).…”

Section: Resultssupporting

confidence: 92%

“…It has been reported previously that, fluoxetine, a selective serotonin reuptake inhibitor, is able to act as an anticancer agent by virtue of its ability to reduce acute murine colitis through inhibition of the NFκB pathway . Recently, fluoxetine has been proposed as an effective anti‐inflammatory/anti‐oxidant agent because of its efficiency to reduce systemic levels of TNF‐α and IL‐6, and scavenge free radicals, respectively . In the present study, we evaluated the role of NFκB in modulating p53 activation status in inflammation‐induced proliferating immune cells.…”

Section: Introductionmentioning

confidence: 94%

“…Recently, it has been established that inflammation is strongly correlated with proliferative responses in cancer . Inflammation‐induced NFκB activation in immune cells has been associated with cancer pathogenesis and maintenance of a proinflammatory environment in the tumor niche . The role of NFκB in the inflammation‐dictated cells toward maintaining a proinflammatory/survival condition by activating the expression of proinflammatory cytokines such as IL‐6, IL‐1β and prosurvival proteins such as Bcl2 has been a talking point for many years now …”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

et al. 2019

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Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti‐inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation‐induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki‐67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB‐p65 nuclear translocation. The Ki‐67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS‐induced proliferative conditions, thereby blocking p53‐dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation‐dictated Ki‐67high thymocytes possibly by modulating the hypothalamus–pituitary–adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation‐biased immune cells, authenticating a novel antiproliferative role of an established drug.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

et al. 2019

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“…This interactive mechanism may explain why the growth rate of certain tumor tissues is faster than other types. iii) Certain studies have revealed that tumor cells induce oxidative stress in stromal cells, thus activating the nuclear factor-κB pathway, hypoxia-inducible factor-1 and reactive oxygen species, which induce each other and cause endothelial cell autophagy and mitochondrial autophagy (13)(14)(15)(16). This produces numerous substrates for oxidative phosphorylation, therefore providing a large amount of continuous energy for tumor cell growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

Zhu

Wang

et al. 2016

Oncology Letters

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Abstract. The present study aimed to systematically analyze alterations in the expression of mitochondrial-associated proteins in human bladder cancer T24 cells co-cultured with tumor-associated human umbilical vein endothelial cells (HUVECs), and to investigate the characteristics of bladder cancer cell energy metabolism. The present study used the following techniques: A co-culture system of T24 cells and HUVECs was constructed using a microfluidic chip as a 3D co-culture system; the concentration of lactic acid in the medium of the cells was determined using an automatic microplate reader; a qualitative analysis of mitochondria-associated protein expression was performed by immunofluorescent staining; and a quantitative analysis of mitochondrial-associated protein expression was conducted using western blotting. The present results revealed that between the control groups (monoculture of T24 cells or HUVECs), the mitochondrial-associated protein fluorescence intensity was increased in the HUVECs compared with the T24 cells. The fluorescence intensity of mitochondrial-associated proteins in the HUVEC control group was increased compared with the HUVECs in the experimental co-culture group. In the T24 cells, the protein fluorescence intensity was increased in the experimental co-culture group compared with the control group. In addition, the expression of mitochondria-associated proteins was increased in HUVECs compared with T24 cells in the control groups, while T24 cells in the experimental co-culture group had an increased expression compared with HUVECs in the experimental group (P<0.05). For T24 cells, the expression of mitochondrial-associated proteins was increased in the experimental group compared with the control group, and contrasting results were observed for the HUVECs (P<0.05). Determination of lactic acid concentration demonstrated that lactic acid concentration was highest in the experimental co-culture group, followed by the T24 control group and the HUVEC control group. In conclusion, the present study demonstrated that energy metabolism of the bladder tumor cells does not parallel the 'Warburg effect', since even under sufficient oxygen conditions the tumor cells still undergo glycolysis. Additionally, bladder tumor cells have an efficient oxidative phosphorylation process, wherein tumor cells promote glycolysis in adjacent interstitial cells, thereby causing increased formation of nutritional precursors. These high-energy metabolites are transferred to adjacent tumor cells in a specified direction and enter the Krebs Cycle. Ultimately, oxidative phosphorylation increases, and sufficient ATP is produced.

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“…Thymuses were isolated from the experimental groups and were carefully minced to obtain single cell suspension of thymocytes following Ghosh et al, 2015. Freshly isolated thymocytes were placed in culture (RPMI 1640) to estimate NO release. 0.5 ml of the culture supernatant was mixed with 0.5 ml of Griess Reagent (1% sulphanilamide and 0.1% naphylethylenediamide dihydrochloride in 3% H3PO4 mixed in equal proportion).…”

Section: Nitric Oxide (No) Release Assaymentioning

confidence: 99%

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

et al. 2016

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Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine

Cited by 56 publications

References 54 publications

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

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Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine

Cited by 56 publications

References 54 publications

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67high) thymocytes

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67high) thymocytes

Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes