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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

Biological sustainability of KB9520. A) Percentage of growth inhibition in REN cells after 1, 2, 4, 8, 16 or 24 hours pre-treatment with 10 nM KB9520 followed by wash-off and continued growth in normal medium for an additional 24 hours. B) Mean number of REN cells pre-exposed for 2 hours to normal medium or 0.4, 2, 10 nM KB9520 followed by wash-off and continued growth for additional 24-, 48- and 72 hours in normal medium, respectively. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.
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Fig3: Biological sustainability of KB9520. A) Percentage of growth inhibition in REN cells after 1, 2, 4, 8, 16 or 24 hours pre-treatment with 10 nM KB9520 followed by wash-off and continued growth in normal medium for an additional 24 hours. B) Mean number of REN cells pre-exposed for 2 hours to normal medium or 0.4, 2, 10 nM KB9520 followed by wash-off and continued growth for additional 24-, 48- and 72 hours in normal medium, respectively. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.

Mentions: Since the in vivo plasma half-life of KB9520 is only approximately 1 hour in mice (data not shown) we decided to investigate the biological sustainability and mechanism of action of KB9520 in vitro to better understand its anti-tumorigenic activity and synergism with cisplatin/pemetrexed in vivo. Firstly, we tested the anti-proliferative response to brief exposures (1, 2, 4, 8, 16 and 24 hours) to 10 nM KB9520 on the ERβ positive REN cells (Figure 3A). An exposure of 2 hours presented significantly (p ≤ 0.05) increased inhibitory activity relative to 1 hour exposure and exposures longer than 8 hours. Successively, the 2 hours exposure to KB9520 was characterized further. Cells were treated with different concentrations of KB9520 (0.4, 2 and 10 nM) for 2 hours followed by wash-off and continued growth in normal medium (without KB9520) for an additional 24, 48 and 72 hours (Figure 3B). Control cultures were maintained in normal medium only. The duration of inhibitory effect on REN cell proliferation sustained for at least 24 hours irrespective of concentration of KB9520 used in the 2-hours pre-treatment period. The largest anti-proliferative effect was, however, observed with the highest KB9520 concentration used. After 24 hours the cells slowly regained proliferative activity and from ~48 hours post KB9520 pre-treatment, their proliferative rates were similar to that of REN cells cultivated in normal medium from start of study.Figure 3


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)

Biological sustainability of KB9520. A) Percentage of growth inhibition in REN cells after 1, 2, 4, 8, 16 or 24 hours pre-treatment with 10 nM KB9520 followed by wash-off and continued growth in normal medium for an additional 24 hours. B) Mean number of REN cells pre-exposed for 2 hours to normal medium or 0.4, 2, 10 nM KB9520 followed by wash-off and continued growth for additional 24-, 48- and 72 hours in normal medium, respectively. 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

Fig3: Biological sustainability of KB9520. A) Percentage of growth inhibition in REN cells after 1, 2, 4, 8, 16 or 24 hours pre-treatment with 10 nM KB9520 followed by wash-off and continued growth in normal medium for an additional 24 hours. B) Mean number of REN cells pre-exposed for 2 hours to normal medium or 0.4, 2, 10 nM KB9520 followed by wash-off and continued growth for additional 24-, 48- and 72 hours in normal medium, respectively. Each graph is representative of three independent experiments. Each point represents mean ± s.d. *p ≤ 0.05.
Mentions: Since the in vivo plasma half-life of KB9520 is only approximately 1 hour in mice (data not shown) we decided to investigate the biological sustainability and mechanism of action of KB9520 in vitro to better understand its anti-tumorigenic activity and synergism with cisplatin/pemetrexed in vivo. Firstly, we tested the anti-proliferative response to brief exposures (1, 2, 4, 8, 16 and 24 hours) to 10 nM KB9520 on the ERβ positive REN cells (Figure 3A). An exposure of 2 hours presented significantly (p ≤ 0.05) increased inhibitory activity relative to 1 hour exposure and exposures longer than 8 hours. Successively, the 2 hours exposure to KB9520 was characterized further. Cells were treated with different concentrations of KB9520 (0.4, 2 and 10 nM) for 2 hours followed by wash-off and continued growth in normal medium (without KB9520) for an additional 24, 48 and 72 hours (Figure 3B). Control cultures were maintained in normal medium only. The duration of inhibitory effect on REN cell proliferation sustained for at least 24 hours irrespective of concentration of KB9520 used in the 2-hours pre-treatment period. The largest anti-proliferative effect was, however, observed with the highest KB9520 concentration used. After 24 hours the cells slowly regained proliferative activity and from ~48 hours post KB9520 pre-treatment, their proliferative rates were similar to that of REN cells cultivated in normal medium from start of study.Figure 3

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