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...
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| Format: | Article |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01269/full |
| _version_ | 1818321435593015296 |
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| author | Monica Benvenuto Rosanna Mattera Joshua Ismaele Sticca Piero Rossi Chiara Cipriani Maria Gabriella Giganti Antonio Volpi Andrea Modesti Laura Masuelli Roberto Bei |
| author_facet | Monica Benvenuto Rosanna Mattera Joshua Ismaele Sticca Piero Rossi Chiara Cipriani Maria Gabriella Giganti Antonio Volpi Andrea Modesti Laura Masuelli Roberto Bei |
| author_sort | Monica Benvenuto |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T10:40:52Z |
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| id | doaj.art-04d6a7ce9de94a61bce09e3a496d5297 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T10:40:52Z |
| publishDate | 2018-11-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-04d6a7ce9de94a61bce09e3a496d52972022-12-21T23:50:30ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-11-01910.3389/fphar.2018.01269420120Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant MesotheliomaMonica Benvenuto0Rosanna Mattera1Joshua Ismaele Sticca2Piero Rossi3Chiara Cipriani4Maria Gabriella Giganti5Antonio Volpi6Andrea Modesti7Laura Masuelli8Roberto Bei9Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, ItalyDepartment of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, ItalyMalignant 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.https://www.frontiersin.org/article/10.3389/fphar.2018.01269/fullpolyphenolAT-101BH3 mimeticmalignant mesotheliomaapoptosisautophagy |
| spellingShingle | Monica Benvenuto Rosanna Mattera Joshua Ismaele Sticca Piero Rossi Chiara Cipriani Maria Gabriella Giganti Antonio Volpi Andrea Modesti Laura Masuelli Roberto Bei Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma Frontiers in Pharmacology polyphenol AT-101 BH3 mimetic malignant mesothelioma apoptosis autophagy |
| 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 | polyphenol AT-101 BH3 mimetic malignant mesothelioma apoptosis autophagy |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01269/full |
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