Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane

Nuvoli, Barbara; Camera, Emanuela; Mastrofrancesco, Arianna; Briganti, Stefania; Galati, Rossella

doi:10.1016/j.freeradbiomed.2017.12.008

Cited by 20 publications

(11 citation statements)

References 58 publications

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“…Measurement of ROS generation was examined by using dichlorodihydrofluorescein diacetate (DCFH-DA) in cells according to previously published procedures. 31 Oxidation of DCFH-DA by ROS converts the molecule to 2’,7’dichlorodihydrofluorescein diacetate (DCF), which is highly fluorescent. Briefly, MSTO cells were plated for 24 h at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence

et al. 2019

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Background: Based on previous observations that the nutraceutical CELLFOOD™ (CF), the ‘physiological modulator’ that aimed to make oxygen available ‘on demand’, inhibits the growth of cancer cells, this study was designed to investigate the role of CF in the regulation of hypoxia-inducible factor 1 alpha (HIF1α) and its correlated proteins, phosphoglycerate kinase 1 and vascular endothelial growth factor. Our idea was that CF, acting on HIF1α, in combination with current anticancer therapies could improve their effectiveness. Methods: To evaluate the effect of CF in association with radiotherapy and chemotherapy, different human cancer cell lines and mice with mesothelioma were analysed by tumour growth, clonogenic assay, western blot and immunohistochemical analysis. Results: CF in combination with radiation with or without cisplatin increases the death rate of cancer cells. In vivo, 70% of mice treated with CF before the mesothelioma graft did not show any tumour growth, indicating a possible preventive effect of CF. Moreover, in mouse mesothelioma xenografts, CF improves the effect of radiotherapy also in combination with chemotherapy treatment. Immunohistochemical analysis of tumour explants showed that HIF1α expression was reduced by the combination of CF and radiotherapy treatment and even more by the combination of CF and radiotherapy and chemotherapy treatment. Mechanistically, CF increases the fraction of oxygenated cells, making the radiotherapy more effective with a greater production of reactive oxygen species (ROS) that in turn, reduce the HIF1α expression. This effect is amplified by further increase in ROS from chemotherapy. Conclusions: Collectively, results from preclinical trials suggest that CF could be a useful intervention to improve the efficacy of radiotherapy or combined treatment strategies and could be a promising treatment modality to counteract cancer.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence

et al. 2019

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“…In our previous report, we indicate an essential role of reactive oxygen species (ROS) in the antiproliferative effect of exemestane in MPM cells, including Ist Me1 and MPP89 cells. In this regard, other studies reported that the action of rofecoxib is associated with an increase of ROS in different cell types [ 52 , 53 ]. Oxidative stress is known to induce p21 expression through a mechanism that is independent of p53 [ 54 ] and this could take place in MPP89 cells.…”

Section: Discussionmentioning

confidence: 93%

“…It is worthy to note that exemestane inhibits proliferation and induces apoptosis in MPM cells through modulation of the Akt/CREB signaling pathway [ 34 , 35 ]. In addition exemestane acts in MPM cells through the generation of ROS, up-regulation of p-ERK and down-regulation of p-STAT [ 52 ]. Bearing this in mind, we thought that AKT and ERK activation could also be targets of rofecoxib in cells that showed a synergistic effect and therefore we investigated the modulation of ERK and AKT activation after treatment with the single inhibitors of COX-2 and CYP19A1 or in combination.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities

Nuvoli

Antoniani

Libener³

et al. 2021

J Exp Clin Cancer Res

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Background Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. Methods The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2. Results PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2. Conclusions Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.

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“…A number of physical treatments or antitumor drugs, such as exemestane (Nuvoli et al, 2018), sorafenib (Roh et al, 2017), cisplatin (Pan et al, 2019), osimertinib (Tang et al, 2017), and irradiation (He et al, 2015), act, at least in part, through the generation of ROS. In this study, we showed that ESI significantly enhanced cisplatin-induced cell death in HCT116 and RKO cells via promoting generation of ROS and activation of the JNK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells

Lin

Chen

et al. 2020

Front. Cell Dev. Biol.

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Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant Elephantopus scaber L., has been reported to exert antitumor effects on several cancer cells. However, the molecular mechanisms underlying the action of ESI is still elusive. In the present study, we found that ESI potently suppressed cell proliferation in human colon cancer cells. Furthermore, our results showed that ESI treatment markedly increased cellular reactive oxygen species (ROS) levels by inhibiting thioredoxin reductase 1 (TrxR1) activity, which leads to activation of the JNK signaling pathway and eventually cell death in HCT116 and RKO cells. Importantly, we found that ESI markedly enhanced cisplatin-induced cytotoxicity in HCT116 and RKO cells. Combination of ESI and cisplatin significantly increased the production of ROS, resulting in activation of the JNK signaling pathway in HCT116 and RKO cells. In vivo, we found that ESI combined with cisplatin significantly suppressed tumor growth in HCT116 xenograft models. Together, our study provide a preclinical proof-of-concept for ESI as a potential strategy for colon cancer treatment.

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Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane

Cited by 20 publications

References 58 publications

RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence

RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence

Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities

Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells

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Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane

Cited by 20 publications

References 58 publications

RETRACTED: The effect of CELLFOODTM on radiotherapy or combined chemoradiotherapy: preclinical evidence

RETRACTED: The effect of CELLFOODTM on radiotherapy or combined chemoradiotherapy: preclinical evidence

Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities

Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells

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Product

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RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence

RETRACTED: The effect of CELLFOOD^TM on radiotherapy or combined chemoradiotherapy: preclinical evidence