Tamoxifen enhances the cytotoxicity of conventional chemotherapy in esophageal adenocarcinoma cells

Due, Steven L.; Watson, David I.; Bastian, Isabell; Ding, Guanxiong; Sukocheva, Olga; Astill, David; Vat, L.; Hussey, Damian J.

doi:10.1016/j.suronc.2016.05.029

Cited by 14 publications

(17 citation statements)

References 49 publications

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“…To the best of our knowledge, this study is the first to investigate the ER status in patients with OC, mainly oesophageal AC from a UK population. It also builds on other studies by Sukocheva et al [ 32 ] and Due et al [ 34 ] where in vitro effects using a selective ER modulator on OC cell lines confirmed anti-proliferative effects observed with Tamoxifen. However, we opted to use only MPP and PHTPP rather than Tamoxifen for an important experimental reason.…”

Section: Discussionsupporting

confidence: 71%

“…For instance, Tamoxifen acts as an ER antagonist on breast tissue and inhibits breast cells proliferation, however it acts as an ER agonist (i.e., mimicking the effects of oestrogen) in bone and uterine cells [ 56 ]. Its action on oesophageal cancer cells used in Sukocheva et al [ 32 ] and Due et al [ 34 ] is not clearly explained whether based on its antagonist or agonist property. In comparison, MPP and PTHPP are highly selective ER antagonists and blocking them allows one to suggest that any experimental effects are likely due to the involvement of these receptors.…”

Section: Discussionmentioning

confidence: 99%

“…ER expression profiles in cancers of the breast, colon, skin, prostate and lung have been investigated extensively [ 26 – 30 ] and a probable role for ER in OC is suggested in a few studies on the basis of protein expression [ 31 , 32 ]. While functional involvement of ER in OC is not well understood, the selective oestrogen modulator (SERM) tamoxifen appears to have an antiproliferative effect and to enhance cytotoxicity of conventional chemotherapy [ 32 – 34 ]. Thus there is a need to further probe mechanisms by which ER contribute to OC progression.…”

Section: Introductionmentioning

confidence: 99%

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Selective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro

et al. 2018

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BackgroundOestrogen receptors (ER) have a well-established role to the initiation, progression and regulation of responses to treatment of breast, prostate, and lung cancers. Previous data indicates altered ER expression in oesophageal cancers (OC). However the role of ER subtypes and ER specific inhibitors in the regulation of OC progression remains unclear. This study sought to assess levels of ERα and ERβ in OC. The effects of highly selective ER antagonists on cell proliferation and apoptosis in two OC adenocarcinoma cell lines was also studied.MethodsERα and ERβ expression profiling in paired normal oesophageal mucosa and tumour tissues (n = 34; adenocarcinoma n = 28; squamous cell carcinoma n = 6) was performed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Correlation between levels of ER with the clinico-pathological features for OC was determined. The effect of selective ER antagonists on proliferation of OE33 and OE19 OC cell lines was studied.ResultsERα and ERβ mRNA expression was significantly higher (p < 0.05) in tumour tissues relative to their paired normal mucosa and correlated inversely with survival outcome (p < 0.05). Upregulation of ERα mRNA correlated with higher pathological T-stage (p < 0.05) and lymph node metastasis (p < 0.05) while ERβ mRNA upregulation correlated with positive vascular invasion (p < 0.05). A significant concentration-dependent inhibition of proliferation in OE33 and OE19 cell lines was induced by a highly-selective ERα antagonist (MPP) and an ERβ specific antagonist (PHTPP) (p < 0.05). Moreover, anti-oestrogens induced cell death through stimulation of apoptotic caspase activity.ConclusionThese findings indicate that the ER system is involved in OC progression and thus may provide a novel target for the treatment of OC.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4030-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro

et al. 2018

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“…Our results were supported by previous studies, where fatostatin was shown to provide anticancer functions in different tumor types, such as pancreatic cancer and lung cancer [31,42]. More importantly, fatostatin was shown to disrupt estrogen-mediated signaling and suppress tumorigenesis in esophageal carcinoma [43][44][45], providing strong support to the current study. However, we believe this is the first report to demonstrate that fatostatin treatment inhibited the self-renewal ability of ESCC stem-like cells.…”

Section: Discussionsupporting

confidence: 91%

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Huang

Hsu

et al. 2019

Cells

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Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Cells 2020, 9, 7 2 of 15Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

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“…The IC 50 of cisplatin, measured via the MTT assay, was 18.5 ± 6.4 µM whilst that of 5-fluorouracil was 14.1 ± 3.8 µM. Both IC 50 values were measured in WHCO1 cells over 24 h. The IC 50 was determined as the concentration of drug needed to kill 50% of cells over 24 h. Similar IC 50 values have been obtained before [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Our preliminary experiments showed that the use of concentrations above 10 µM would result in considerable cell death, and we used concentrations less than half the IC 50 value ( Supplementary Figure S1A–C ).…”

Section: Resultssupporting

confidence: 69%

Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

et al. 2018

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Background: Environmental pollution such as exposure to pro-carcinogens including benzo-α-pyrene is becoming a major problem globally. Moreover, the effects of benzo-α-pyrene (BaP) on drug pharmacokinetics, pharmacodynamics, and drug resistance warrant further investigation, especially in cancer outpatient chemotherapy where exposure to environmental pollutants might occur. Method: We report here on the effects of benzo-α-pyrene on esophageal cancer cells in vitro, alone, or in combination with chemotherapeutic drugs cisplatin, 5-flurouracil, or paclitaxel. As the study endpoints, we employed expression of proteins involved in cell proliferation, drug metabolism, apoptosis, cell cycle analysis, colony formation, migration, and signaling cascades in the WHCO1 esophageal cancer cell line after 24 h of treatment. Results: Benzo-α-pyrene had no significant effect on WHCO1 cancer cell proliferation but reversed the effect of chemotherapeutic drugs by reducing drug-induced cell death and apoptosis by 30–40% compared to drug-treated cells. The three drugs significantly reduced WHCO1 cell migration by 40–50% compared to control and BaP-treated cells. Combined exposure to drugs was associated with significantly increased apoptosis and reduced colony formation. Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs. Conclusion: The present study suggest that BaP can reverse the effects of drugs on cancer cells via the activation of survival signaling pathways and upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Our data show that BaP contribute to the development of chemoresistant cancer cells.

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Tamoxifen enhances the cytotoxicity of conventional chemotherapy in esophageal adenocarcinoma cells

Cited by 14 publications

References 49 publications

Selective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro

Selective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

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