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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 sensitizes REN cells to cisplatin and the standard of care chemo combination. Effect on REN cell viability after 2 hours pre-treatment with KB9520 (10nM) followed by wash-off and continued growth in normal medium supplemented with different concentrations of A) cisplatin (20–100 μM), for additional 24 hours, B) pemetrexed (5–22 μM), for additional 24 hours and C) cisplatin (100 μM) or the cisplatin (100 μM)/pemetrexed (22 μM) combination, for an additional 24 hours. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.
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Fig5: KB9520 sensitizes REN cells to cisplatin and the standard of care chemo combination. Effect on REN cell viability after 2 hours pre-treatment with KB9520 (10nM) followed by wash-off and continued growth in normal medium supplemented with different concentrations of A) cisplatin (20–100 μM), for additional 24 hours, B) pemetrexed (5–22 μM), for additional 24 hours and C) cisplatin (100 μM) or the cisplatin (100 μM)/pemetrexed (22 μM) combination, for an additional 24 hours. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.

Mentions: To explore the sequence of drug administration and its effect on cell proliferation we performed add-on or wash-off experiments (Figures 4 and 5). In the first study 100 μM cisplatin was added to REN cell cultures pre-treated for 2, 4, 8 and 12 hours with 10 nM KB9520 (Figure 4A). The enhanced anti-proliferative effect of cisplatin was time-dependent with the greatest inhibitory effect obtained adding cisplatin within 2 hours of KB9520 pre-treatment.


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 sensitizes REN cells to cisplatin and the standard of care chemo combination. Effect on REN cell viability after 2 hours pre-treatment with KB9520 (10nM) followed by wash-off and continued growth in normal medium supplemented with different concentrations of A) cisplatin (20–100 μM), for additional 24 hours, B) pemetrexed (5–22 μM), for additional 24 hours and C) cisplatin (100 μM) or the cisplatin (100 μM)/pemetrexed (22 μM) combination, for an additional 24 hours. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: KB9520 sensitizes REN cells to cisplatin and the standard of care chemo combination. Effect on REN cell viability after 2 hours pre-treatment with KB9520 (10nM) followed by wash-off and continued growth in normal medium supplemented with different concentrations of A) cisplatin (20–100 μM), for additional 24 hours, B) pemetrexed (5–22 μM), for additional 24 hours and C) cisplatin (100 μM) or the cisplatin (100 μM)/pemetrexed (22 μM) combination, for an additional 24 hours. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.
Mentions: To explore the sequence of drug administration and its effect on cell proliferation we performed add-on or wash-off experiments (Figures 4 and 5). In the first study 100 μM cisplatin was added to REN cell cultures pre-treated for 2, 4, 8 and 12 hours with 10 nM KB9520 (Figure 4A). The enhanced anti-proliferative effect of cisplatin was time-dependent with the greatest inhibitory effect obtained adding cisplatin within 2 hours of KB9520 pre-treatment.

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