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Article

OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence

1
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
2
Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
3
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
4
Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Stefania Rizzo, Lucia Manganaro and Robert C. Bast
Cancers 2021, 13(7), 1519; https://doi.org/10.3390/cancers13071519
Received: 15 February 2021 / Revised: 10 March 2021 / Accepted: 19 March 2021 / Published: 25 March 2021
(This article belongs to the Special Issue Omics in Ovarian Cancer)
The outcome for women diagnosed with ovarian cancer (OC), the most aggressive gynecological tumor worldwide, remains very poor. Encouraging therapeutic impact of epigenetic drugs has been suggested in a wide range of human solid tumors, including OC. The present study assessed the in vitro cytostatic and cytotoxic effects of OTX015, a pan Bromodomain and Extra-Terminal motif inhibitor, in human OC cells, both as single treatment and in combination with radiotherapy. Cellular, molecular and computational network analyses indicated the centrality of GNL3 downregulation in mediating the OTX015-related antitumor efficacy that blocks disease progression/maintenance and radioresistance acquisition. Our preclinical results confirm that targeted and combinatorial treatments represent effective anticancer strategies to be translated in the clinical research for improving OC patient care.
Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC. View Full-Text
Keywords: BET inhibitors; OTX015; ovarian cancer; GNL3 (nucleostemin); radioresistance BET inhibitors; OTX015; ovarian cancer; GNL3 (nucleostemin); radioresistance
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MDPI and ACS Style

Megiorni, F.; Camero, S.; Pontecorvi, P.; Camicia, L.; Marampon, F.; Ceccarelli, S.; Anastasiadou, E.; Bernabò, N.; Perniola, G.; Pizzuti, A.; Benedetti Panici, P.; Tombolini, V.; Marchese, C. OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence. Cancers 2021, 13, 1519. https://doi.org/10.3390/cancers13071519

AMA Style

Megiorni F, Camero S, Pontecorvi P, Camicia L, Marampon F, Ceccarelli S, Anastasiadou E, Bernabò N, Perniola G, Pizzuti A, Benedetti Panici P, Tombolini V, Marchese C. OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence. Cancers. 2021; 13(7):1519. https://doi.org/10.3390/cancers13071519

Chicago/Turabian Style

Megiorni, Francesca, Simona Camero, Paola Pontecorvi, Lucrezia Camicia, Francesco Marampon, Simona Ceccarelli, Eleni Anastasiadou, Nicola Bernabò, Giorgia Perniola, Antonio Pizzuti, Pierluigi Benedetti Panici, Vincenzo Tombolini, and Cinzia Marchese. 2021. "OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence" Cancers 13, no. 7: 1519. https://doi.org/10.3390/cancers13071519

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