Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists
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Loredana Urso1, Ilaria Cavallari2,*, Micol Silic-Benussi2,*, Lorena Biasini2, Giulia Zago3, Fiorella Calabrese4, Pier Franco Conte1,3, Vincenzo Ciminale1,2 and Giulia Pasello3
1Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128, Padova, Italy
2Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IRCCS, 35128, Padova, Italy
3Medical Oncology Unit 2, Veneto Institute of Oncology, IRCCS, 35128, Padova, Italy
4Department of Cardio-Thoracic and Vascular Sciences, University of Padova, 35128, Padova, Italy
*These authors contributed equally to this work
Vincenzo Ciminale, email: [email protected]
Keywords: mesothelioma, MDM2, p53, RG7112, TRAIL
Received: March 10, 2017 Accepted: April 24, 2017 Published: May 11, 2017
Malignant Pleural Mesothelioma (MPM) is a chemoresistant tumor characterized by low rate of p53 mutation and upregulation of Murine Double Minute 2 (MDM2), suggesting that it may be effectively targeted using MDM2 inhibitors. In the present study, we investigated the anticancer activity of the MDM2 inhibitors Nutlin 3a (in vitro) and RG7112 (in vivo), as single agents or in combination with rhTRAIL.
In vitro studies were performed using MPM cell lines derived from epithelioid (ZL55, M14K), biphasic (MSTO211H) and sarcomatoid (ZL34) MPMs. In vivo studies were conducted on a sarcomatoid MPM mouse model.
In all the cell lines tested (with the exception of ZL55, which carries a biallelic loss-of-function mutation of p53), Nutlin 3a enhanced p21, MDM2 and DR5 expression, and decreased survivin expression. These changes were associated to cell cycle arrest but not to a significant induction of apoptosis. A synergistic pro-apoptotic effect was obtained through the association of rhTRAIL in all the cell lines harboring functional p53. This synergistic interaction of MDM2 inhibitor and TRAIL agonist was confirmed using a mouse preclinical model. Our results suggest that the combined targeting of MDM2 and TRAIL might provide a novel therapeutic option for treatment of MPM patients, particularly in the case of sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53.
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