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

Pinton G, Manente AG, Daga A, Cilli M, Rinaldi M, Nilsson S, Moro L - Mol. Cancer (2014)

Bottom Line: KB9520 showed significant anti-proliferative effect in ERβ positive human malignant pleural mesothelioma cells in vitro.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A, Avogadro", Lgo Donegani 2, 28100 Novara, Italy. moro@pharm.unipmn.it.

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.

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Related in: MedlinePlus

KB9520 significantly increases cisplatin/pemetrexed effectsin vitroandin vivo. A) Percentage of viable REN cells exposed for 24 hours to 10 nM KB9520 alone or in combination with cisplatin (100 μM) and pemetrexed (22 μM), versus untreated cells. Graph is representative of three independent experiments. Each bar represents mean ± s.d. *p ≤ 0.05. B) and C) Box plots of the 4 different treatment groups (10 mice/group) showing in vivo mean tumor growth (B) and mean tumor growth inhibition (C) evaluated after 21 days of treatment. The thick segments represent the medians while the upper and lower borders of each rectangle represent the quartiles. Bars show minimum and maximum values for each group, outliers are identified by a small circle. Kruskal-Wallis rank sum test (in B) confirms that combination treatment significantly reduced tumor growth, compared with control or single treatments.
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Fig2: KB9520 significantly increases cisplatin/pemetrexed effectsin vitroandin vivo. A) Percentage of viable REN cells exposed for 24 hours to 10 nM KB9520 alone or in combination with cisplatin (100 μM) and pemetrexed (22 μM), versus untreated cells. Graph is representative of three independent experiments. Each bar represents mean ± s.d. *p ≤ 0.05. B) and C) Box plots of the 4 different treatment groups (10 mice/group) showing in vivo mean tumor growth (B) and mean tumor growth inhibition (C) evaluated after 21 days of treatment. The thick segments represent the medians while the upper and lower borders of each rectangle represent the quartiles. Bars show minimum and maximum values for each group, outliers are identified by a small circle. Kruskal-Wallis rank sum test (in B) confirms that combination treatment significantly reduced tumor growth, compared with control or single treatments.

Mentions: To test if KB9520 influences MPM cell response to chemotherapy in vitro, we explored the effect of adding 10 nM KB9520 to the cisplatin/pemetrexed chemo combination (at their respective IC50 concentrations) on REN cell viability. As shown in Figure 2A, the triple combination KB9520/cisplatin/pemetrexed (10 nM/100 μM/22 μM, respectively) was superior (p ≤ 0.05) to either KB9520 or cisplatin/pemetrexed treatment alone.Figure 2


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

Pinton G, Manente AG, Daga A, Cilli M, Rinaldi M, Nilsson S, Moro L - Mol. Cancer (2014)

KB9520 significantly increases cisplatin/pemetrexed effectsin vitroandin vivo. A) Percentage of viable REN cells exposed for 24 hours to 10 nM KB9520 alone or in combination with cisplatin (100 μM) and pemetrexed (22 μM), versus untreated cells. Graph is representative of three independent experiments. Each bar represents mean ± s.d. *p ≤ 0.05. B) and C) Box plots of the 4 different treatment groups (10 mice/group) showing in vivo mean tumor growth (B) and mean tumor growth inhibition (C) evaluated after 21 days of treatment. The thick segments represent the medians while the upper and lower borders of each rectangle represent the quartiles. Bars show minimum and maximum values for each group, outliers are identified by a small circle. Kruskal-Wallis rank sum test (in B) confirms that combination treatment significantly reduced tumor growth, compared with control or single treatments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197308&req=5

Fig2: KB9520 significantly increases cisplatin/pemetrexed effectsin vitroandin vivo. A) Percentage of viable REN cells exposed for 24 hours to 10 nM KB9520 alone or in combination with cisplatin (100 μM) and pemetrexed (22 μM), versus untreated cells. Graph is representative of three independent experiments. Each bar represents mean ± s.d. *p ≤ 0.05. B) and C) Box plots of the 4 different treatment groups (10 mice/group) showing in vivo mean tumor growth (B) and mean tumor growth inhibition (C) evaluated after 21 days of treatment. The thick segments represent the medians while the upper and lower borders of each rectangle represent the quartiles. Bars show minimum and maximum values for each group, outliers are identified by a small circle. Kruskal-Wallis rank sum test (in B) confirms that combination treatment significantly reduced tumor growth, compared with control or single treatments.
Mentions: To test if KB9520 influences MPM cell response to chemotherapy in vitro, we explored the effect of adding 10 nM KB9520 to the cisplatin/pemetrexed chemo combination (at their respective IC50 concentrations) on REN cell viability. As shown in Figure 2A, the triple combination KB9520/cisplatin/pemetrexed (10 nM/100 μM/22 μM, respectively) was superior (p ≤ 0.05) to either KB9520 or cisplatin/pemetrexed treatment alone.Figure 2

Bottom Line: KB9520 showed significant anti-proliferative effect in ERβ positive human malignant pleural mesothelioma cells in vitro.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A, Avogadro", Lgo Donegani 2, 28100 Novara, Italy. moro@pharm.unipmn.it.

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.

Show MeSH
Related in: MedlinePlus