Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity

Our plain-English summary of Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity, by G. Pinton, A.G. Manente, A. Daga, et al (Molecular Cancer, 2014).

The study

• Authors: G. Pinton, A.G. Manente, A. Daga, M. Cilli, M. Rinaldi, S. Nilsson, L. Moro
• Journal: Molecular Cancer
• Published: 2014;13:227
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Estrogen receptor (ER) β acts as a tumor suppressor in malignant mesotheliomas.

Methods: Here we explored the anti-proliferative and anti-tumorigenic efficacy of the selective ERβ agonist, KB9520, in human mesothelioma cell lines in vitro and in a mesothelioma mouse model in vivo.

Results: KB9520 showed significant anti-proliferative effect in ERβ positive human malignant pleural mesothelioma cells in vitro. Selective activation of ERβ with KB9520 sensitized the cells to treatment with cisplatin, resulting in enhanced growth inhibition and increased apoptosis. Furthermore, in CD1 nude mice mesothelioma tumor growth was significantly inhibited when KB9520 was added on top of the standard of care chemo combination cisplatin/pemetrexed, as compared to the cisplatin/pemetrexed alone group. Importantly, KB9520 exerted a protective effect to cisplatin toxicity in the non-malignant mesothelium derived MET5A cells.

Conclusions: Together, the data presented suggest that selective targeting of ERβ may be an efficacious stand-alone treatment option and/or become an important add-on to existing malignant mesothelioma therapy.

In plain English

This laboratory study tested KB9520, an experimental drug that selectively activates estrogen receptor beta (ERβ), on human malignant pleural mesothelioma cell lines and in mice. It did not study asbestos exposure. In cell cultures, KB9520 significantly slowed the growth of REN and MMB mesothelioma cells but did not slow non-malignant mesothelium-derived MET5A cells. ERβ-negative cells and cells with ERβ silenced did not respond. On REN cells, KB9520 plus cisplatin and pemetrexed worked better than either treatment alone. Giving KB9520 before cisplatin strengthened cisplatin's effect, but giving cisplatin first did not. With KB9520, 20 micromolar cisplatin was as effective as 100 micromolar cisplatin alone. KB9520 added nothing to pemetrexed alone. With KB9520 then cisplatin, 22 percent of REN cells were dead, versus 8 percent with cisplatin alone. In MET5A cells, KB9520 had a protective effect against low cisplatin concentrations. In mice with REN tumors in the abdomen (10 per group), tumor growth was significantly lower with KB9520 plus cisplatin/pemetrexed than in the other three groups. The authors concluded that selectively activating ERβ can suppress mesothelioma cell and tumor growth.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on human cell lines (in vitro) and a mouse tumor model (in vivo)
• Who was studied: Human malignant mesothelioma cell lines REN, MMB, H2596 and MSTO-211H, and the non-malignant mesothelium-derived MET5A cell line. Also six-week-old male CD1 nude mice injected in the peritoneum with REN cells, in 4 groups of 10 animals.
• Exposure: No asbestos exposure was studied. The treatments were the ERβ agonist KB9520, cisplatin and pemetrexed. In mice: KB9520 10 mg/kg/day by injection under the skin on days 15 to 35; cisplatin 5 mg/kg on days 18 and 25; pemetrexed 150 mg/kg on days 19 to 23 and 26 to 30.
• Main results:
  • KB9520 significantly inhibited proliferation of REN and MMB mesothelioma cells but had no inhibitory effect on non-malignant MET5A cells
  • ERβ-negative MSTO-211H cells, and REN and MMB cells with ERβ silenced, did not respond to KB9520
  • In REN cells, the combination of KB9520, cisplatin and pemetrexed was superior to KB9520 alone or to cisplatin/pemetrexed alone
  • In REN cells, giving cisplatin first and then KB9520 did not produce synergistic growth inhibition
  • In REN cells, 2 hours of KB9520 pre-treatment plus 20 micromolar cisplatin was as effective as 100 micromolar cisplatin alone
  • In REN cells, KB9520 combined with pemetrexed alone showed no synergistic or additive effect
  • In REN cells, the percentage of dead cells was higher after KB9520 pre-treatment followed by cisplatin than with the other treatments (Table 2: 22 with the combination, 8 with cisplatin alone, 8 with KB9520 alone, 3 in controls)
  • In non-malignant MET5A cells, KB9520 pre-treatment had a protective effect when combined with low cisplatin concentrations
  • In mice, after 21 days of treatment, tumor growth was significantly lower in the KB9520 plus cisplatin/pemetrexed group than in the vehicle, KB9520-alone and cisplatin/pemetrexed groups (10 mice per group)
• The authors' conclusion: The authors concluded that mesothelioma cell proliferation and tumor growth can be effectively suppressed by selective activation of ERβ
• Limitations the authors state:
  • The authors stated that the lack of effect of KB9520 on the ERβ-positive non-malignant MET5A cells is difficult to understand and needs further investigation
  • The authors stated that the observed reduction in AKT phosphorylation needs further investigation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Mesothelioma, Apoptosis, Pemetrexed (Alimta), Mesothelium.

Related studies

• Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells — A.G. Manente, G. Pinton, et al. (2015)
• Estrogen receptor-beta affects the prognosis of human malignant mesothelioma — G. Pinton, E. Brunelli, et al. (2009)
• Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin — Y. Shi, E. Felley-Bosco, et al. (2012)
• Estrogen receptor β exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib — G. Pinton, W. Thomas, et al. (2010)
• KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma — A.G. Manente, G. Pinton, et al. (2016)
• Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo — A.G. Manente, D. Valenti, et al. (2013)

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