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Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma
Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting mult...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232343/ https://www.ncbi.nlm.nih.gov/pubmed/30459622 http://dx.doi.org/10.3389/fphar.2018.01269 |
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author | Benvenuto, Monica Mattera, Rosanna Sticca, Joshua Ismaele Rossi, Piero Cipriani, Chiara Giganti, Maria Gabriella Volpi, Antonio Modesti, Andrea Masuelli, Laura Bei, Roberto |
author_facet | Benvenuto, Monica Mattera, Rosanna Sticca, Joshua Ismaele Rossi, Piero Cipriani, Chiara Giganti, Maria Gabriella Volpi, Antonio Modesti, Andrea Masuelli, Laura Bei, Roberto |
author_sort | Benvenuto, Monica |
collection | PubMed |
description | Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies. |
format | Online Article Text |
id | pubmed-6232343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62323432018-11-20 Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma Benvenuto, Monica Mattera, Rosanna Sticca, Joshua Ismaele Rossi, Piero Cipriani, Chiara Giganti, Maria Gabriella Volpi, Antonio Modesti, Andrea Masuelli, Laura Bei, Roberto Front Pharmacol Pharmacology Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies. Frontiers Media S.A. 2018-11-06 /pmc/articles/PMC6232343/ /pubmed/30459622 http://dx.doi.org/10.3389/fphar.2018.01269 Text en Copyright © 2018 Benvenuto, Mattera, Sticca, Rossi, Cipriani, Giganti, Volpi, Modesti, Masuelli and Bei. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Benvenuto, Monica Mattera, Rosanna Sticca, Joshua Ismaele Rossi, Piero Cipriani, Chiara Giganti, Maria Gabriella Volpi, Antonio Modesti, Andrea Masuelli, Laura Bei, Roberto Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title | Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title_full | Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title_fullStr | Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title_full_unstemmed | Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title_short | Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma |
title_sort | effect of the bh3 mimetic polyphenol (–)-gossypol (at-101) on the in vitro and in vivo growth of malignant mesothelioma |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232343/ https://www.ncbi.nlm.nih.gov/pubmed/30459622 http://dx.doi.org/10.3389/fphar.2018.01269 |
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