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2. Supplementary Figures 1-7, Table 1 and Methods. from Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids

Author

Vernon, Mégane, primary, Lambert, Bernard, primary, Meryet-Figuière, Matthieu, primary, Brotin, Emilie, primary, Weiswald, Louis-Bastien, primary, Paysant, Hippolyte, primary, Vigneron, Nicolas, primary, Wambecke, Anaïs, primary, Abeilard, Edwige, primary, Giffard, Florence, primary, Louis, Marie-Hélène, primary, Blanc-Fournier, Cécile, primary, Gauduchon, Pascal, primary, Poulain, Laurent, primary, and Denoyelle, Christophe, primary

Published
2023
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7. Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids

Author

Vernon, Mégane, primary, Lambert, Bernard, additional, Meryet-Figuière, Matthieu, additional, Brotin, Emilie, additional, Weiswald, Louis-Bastien, additional, Paysant, Hippolyte, additional, Vigneron, Nicolas, additional, Wambecke, Anaïs, additional, Abeilard, Edwige, additional, Giffard, Florence, additional, Louis, Marie-Hélène, additional, Blanc-Fournier, Cécile, additional, Gauduchon, Pascal, additional, Poulain, Laurent, additional, and Denoyelle, Christophe, additional

Published
2020
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8. Predictive Relevance of Circulating miR-622 in Patients with Newly Diagnosed and Recurrent High-Grade Serous Ovarian Carcinoma

Author

Vigneron, Nicolas, primary, Vernon, Mégane, additional, Meryet-Figuière, Matthieu, additional, Lambert, Bernard, additional, Briand, Mélanie, additional, Louis, Marie-Hélène, additional, Krieger, Sophie, additional, Joly, Florence, additional, Lheureux, Stéphanie, additional, Blanc-Fournier, Cécile, additional, Gauduchon, Pascal, additional, Poulain, Laurent, additional, and Denoyelle, Christophe, additional

Published
2020
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10. Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation

Author

Bonnefond, Marie-Laure, Florent, Romane, Lenoir, Sophie, Lambert, Bernard, Abeilard, Edwige, Giffard, Florence, Louis, Marie-Hélène, Elie, Nicolas, Briand, Mélanie, Vivien, Denis, Poulain, Laurent, Gauduchon, Pascal, N'Diaye, Monique, Axe BioTICLA, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-CHU Caen, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Délégation Régionale Normandie du CNRS [Caen], Centre de Microscopie Appliquée à la Biologie [Caen] (CMABio3), Interactions Cellules Organismes Environnement (ICORE), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), The research was supported by the Ligue Contre le Cancer (Comité départemental de l’Orne). Marie-Laure Bonnefond and Romane Florent were funded by a grant from Normandy Regional Council and Marie-Laure Bonnefond was also funded by Accord Healthcare Inc., Bodescot, Myriam, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-CHU Caen, and Normandie Université (NU)

Subjects
ovarian cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Store-operated calcium channels, ABT-737, [SDV.CAN]Life Sciences [q-bio]/Cancer, MCL-1, mTORC1
Abstract

International audience; The anti-apoptotic proteins Bcl-xL and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-xL activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-xL strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-xL strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma.

Published
2018

11. Atelocollagen-mediated in vivo siRNA transfection in ovarian carcinoma is influenced by tumor site, siRNA target and administration route

Author

Meryet-Figuière, Matthieu, Lecerf, Charlotte, Varin, Emilie, Coll, Jean-Luc, Louis, Marie-Hélène, Dutoit, Soizic, Giffard, Florence, Blanc-Fournier, Cécile, Hedir, Siham, Vigneron, Nicolas, Brotin, Emilie, Pelletier, Laurent, Josserand, Veronique, Denoyelle, Christophe, Poulain, Laurent, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), The present study is part of the national program Cartes d'Identité des Tumeurs (CIT) funded and developed by the Ligue NationaleContre le Cancer. It was supported by the ‘Ligue contrele Cancer’ (Calvados and Orne Committee), the ‘ConseilRegional de Basse-Normandie’, and the French Government.E.B., M.M.F., E.V. and C.L. were recipients of a doctoralfellowship from the ‘Ligue contre le Cancer’ (CalvadosCommittee: E.B., E.V. and C.L., Eure Committee: M.M.F.)and C.D. was recipient of a post-doctoral fellowship from the‘Conseil Regional de Basse-Normandie’. N.V. was a recipientof a doctoral fellowship from the French Ministry for HigherEducation and Research. The present study was supported by agrant from l'Ecole de l'Inserm Liliane Bettencourt (N.V.)., Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Duchange, Nathalie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER

Subjects
Genetic Vectors, bcl-X Protein, in vivo transfection, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, Mice, Random Allocation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bcl-2 family, Cell Line, Tumor, Animals, Humans, RNA, Small Interfering, Luciferases, Ovarian Neoplasms, Carcinoma, Articles, Xenograft Model Antitumor Assays, ovarian cancer, siRNA, Luminescent Measurements, Myeloid Cell Leukemia Sequence 1 Protein, Female, Collagen, atelocollagen
Abstract

International audience; Ovarian cancer is the leading cause of death from gynecological malignancies worldwide, and innate or acquired chemoresistance of ovarian cancer cells is the major cause of therapeutic failure. It has been demonstrated that the concomitant inhibition of Bcl-x L and Mcl-1 anti-apoptotic activities is able to trigger apoptosis in chemoresistant ovarian cancer cells. In this context, siRNA-mediated Bcl-x L and Mcl-1 inhibition constitutes an appealing strategy by which to eliminate chemoresistant cancer cells. However, the safest and most efficient way to vectorize siRNAs in vivo is still under debate. In the present study, using in vivo bioluminescence imaging, we evaluated the interest of atelocollagen to vectorize siRNAs by intraperitoneal (i.p.) or intravenous (i.v.) administration in 2 xenografted ovarian cancer models (peritoneal carcinomatosis and subcutaneous tumors in nude mice). Whereas i.p. administration of atelocollagen-vectorized siRNA in the peritoneal carcinomatosis model did not induce any gene downregulation, a 70% transient downregulation of luciferase expression was achieved after i.v. injection of atelocollagen-vectorized siRNA in the subcutaneous (s.c.) model. However, the use of siRNA targeting Bcl-x L or Mcl-1 did not induce target-specific downregulation in vivo in nude mice. Our results therefore show that atelocollagen complex formulation, the administration route, tumor site and the identity of the siRNA target influence the efficiency of atelocollagen-mediated siRNA delivery.

Published
2017

13. The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737

Author

Pétigny-Lechartier, Cécile, primary, Duboc, Charlène, additional, Jebahi, Abdelghani, additional, Louis, Marie-Hélène, additional, Abeilard, Edwige, additional, Denoyelle, Christophe, additional, Gauduchon, Pascal, additional, Poulain, Laurent, additional, and Villedieu, Marie, additional

Published
2017
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14. Towards a new standardized method for circulating miRNAs profiling in clinical studies: Interest of the exogenous normalization to improve miRNA signature accuracy

Author

Vigneron, Nicolas, primary, Meryet-Figuière, Matthieu, additional, Guttin, Audrey, additional, Issartel, Jean-Paul, additional, Lambert, Bernard, additional, Briand, Mélanie, additional, Louis, Marie-Hélène, additional, Vernon, Mégane, additional, Lebailly, Pierre, additional, Lecluse, Yannick, additional, Joly, Florence, additional, Krieger, Sophie, additional, Lheureux, Stéphanie, additional, Clarisse, Bénédicte, additional, Leconte, Alexandra, additional, Gauduchon, Pascal, additional, Poulain, Laurent, additional, and Denoyelle, Christophe, additional

Published
2016
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15. Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies

Author

Philippe, Icard, Icard, Philippe, Xiao-Dong, Zhang, Zhang, Xiao-Dong, Edwige, Lemoisson, Lemoisson, Edwige, Marie-Hélène, Louis, Louis, Marie-Hélène, Stéphane, Allouche, Allouche, Stéphane, Hubert, Lincet, Lincet, Hubert, Laurent, Poulain, and Poulain, Laurent

Subjects
Mesothelioma, Necrosis, Physiology, Cell Survival, Blotting, Western, Mice, Nude, Apoptosis, In Vitro Techniques, Models, Biological, Mice, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Pyruvates, Cisplatin, Dose-Response Relationship, Drug, Chemistry, Cell Biology, medicine.disease, Flow Cytometry, Mitochondria, Proto-Oncogene Proteins c-bcl-2, Toxicity, Immunology, Cancer cell, Cancer research, Peritoneal mesothelioma, Myeloid Cell Leukemia Sequence 1 Protein, Female, medicine.symptom, Metabolic Networks and Pathways, medicine.drug
Abstract

Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the “Warburg effect”, to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.

Published
2011

16. First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-xL-Targeting Strategies

Author

Gloaguen, Céline, primary, Voisin-Chiret, Anne Sophie, additional, Sopkova-de Oliveira Santos, Jana, additional, Fogha, Jade, additional, Gautier, Fabien, additional, De Giorgi, Marcella, additional, Burzicki, Grégory, additional, Perato, Serge, additional, Pétigny-Lechartier, Cécile, additional, Simonin-Le Jeune, Karin, additional, Brotin, Emilie, additional, Goux, Didier, additional, N’Diaye, Monique, additional, Lambert, Bernard, additional, Louis, Marie-Hélène, additional, Ligat, Laetitia, additional, Lopez, Frédéric, additional, Juin, Philippe, additional, Bureau, Ronan, additional, Rault, Sylvain, additional, and Poulain, Laurent, additional

Published
2015
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18. 18F-FDG Is a Surrogate Marker of Therapy Response and Tumor Recovery after Drug Withdrawal during Treatment with a Dual PI3K/mTOR Inhibitor in a Preclinical Model of Cisplatin-Resistant Ovarian Cancer

Author

Lheureux, Stéphanie, primary, Lecerf, Charlotte, additional, Briand, Mélanie, additional, Louis, Marie-Hélène, additional, Dutoit, Soizic, additional, Jebahi, Abdelghani, additional, Giffard, Florence, additional, Fournier, Cécile Blanc, additional, Batalla, Alain, additional, Poulain, Laurent, additional, and Aide, Nicolas, additional

Published
2013
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21. Inhibition of Mcl-1 expression by citrate enhances the effect of Bcl-xL inhibitors on human ovarian carcinoma cells.

Author

Lincet, Hubert, Kafara, Perrine, Giffard, Florence, Abeilard-Lemoisson, Edwige, Duval, Maryline, Louis, Marie-Hélène, Poulain, Laurent, and Icard, Philippe

Subjects
CANCER cells, OVARIAN cancer, CITRATES, GENE expression, APOPTOTIC protease-activating factor 1
Abstract

The inhibition of two major anti-apoptotic proteins, Bcl-xL and Mcl-1, appears essential to destroy chemoresistant cancer cells. We have studied their concomitant inhibition, using ABT 737 or siRNA targeting XL1 and citrate, a molecule which reduces the expression level of Mcl-1. Two cisplatin-chemoresistant ovarian cell lines (SKOV3 and IGROV1-R10) were exposed to ABT 737 or siRNA targeting XL1 and citrate at various individual concentrations, or combined. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. Mcl-1 expression was barely reduced when cells were exposed to citrate alone, whereas a mild reduction was observed after ABT 737 treatment. Concomitant inhibition of Bcl-xL and Mcl-1 using ABT 737 or siXL1 associated with citrate was far more effective in inhibiting cell proliferation and inducing cell death than treatment alone. Given that few, if any, specific inhibitors of Mcl-1 are currently available, anti-glycolytic agents such as citrate could be tested in association with synthetic inhibitors of Bcl-xL [ABSTRACT FROM AUTHOR]

Published
2013
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22. Sensitization of ovarian carcinoma cells to Bcl-xL-targeting strategies through indirect modulation of Mcl-1 activity by MR22388, a molecule of the tripentone family.

Author

Tomasina, Julie, Malzert-Freon, Aurélie, Giffard, Florence, Brotin, Emilie, Louis, Marie-Hélène, Abeilard, Edwige, Rault, Sylvain, Gauduchon, Pascal, and Poulain, Laurent

Subjects
TRANSFER factor (Immunology), CARCINOMA, CANCER cells, PLATINUM, GUAIACOL, CANCER chemotherapy, GROWTH factors
Abstract

Background: Our work has been carried out in the context of the therapeutic failure in ovarian carcinoma, which remains the leading cause of death by gynecologic malignancy. In these tumours, recurrence and subsequent acquired chemoresistance constitute major hurdles to successful therapy. Here we studied the interest of a member of the tripentone chemical family, MR22388, for the treatment of chemoresistant ovarian cancer cells. Findings: MR22388 activity has been assessed in vitro on cisplatin-resistant (SKOV3 and IGROV1-R10) ovarian cancer cell lines by conventional analysis, alone or combined to a BH3-mimetic molecule, ABT-737. MR22388 exerts its activity on cisplatin resistant cells, and we showed that it induces a decrease of the Mcl-1 anti-apoptotic protein expression. Considering our previous work demonstrating that the efficiency of Bcl-xL targeting strategies is conditioned to the concomitant inhibition of Mcl-1 we studied the interest of the association of this MR22388 with ABT-737, and showed that this combination was highly cytotoxic in chemoresistant cells. Conclusions: This work thus opens new perspectives for the use of this promising molecule for the treatment of highly chemoresistant ovarian cancer cells and for sensitization of emerging Bcl-xL targeting strategies such as the use of BH3-mimetic molecules. [ABSTRACT FROM AUTHOR]

Published
2013
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23. PI3K/mTOR dual inhibitor NVP-BEZ235 decreases Mcl-1 expression and sensitizes ovarian carcinoma cells to Bcl-xL-targeting strategies, provided that Bim expression is induced.

Author

Jebahi, Abdelghani, Villedieu, Marie, Pétigny-Lechartier, Cécile, Brotin, Emilie, Louis, Marie-Hélène, Abeilard, Edwige, Giffard, Florence, Guercio, Marika, Briand, Mélanie, Gauduchon, Pascal, Lheureux, Stéphanie, and Poulain, Laurent

Subjects
*PHOSPHOINOSITIDES, *MTOR protein, *GENE expression, *OVARIAN cancer treatment, *CANCER cells, *APOPTOSIS, *B cells
Abstract

Abstract: We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment. [Copyright &y& Elsevier]

Published
2014
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24. Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-Bclx L strategies through Mcl-1 down-regulation.

Author

Bonnefond ML, Florent R, Lenoir S, Lambert B, Abeilard E, Giffard F, Louis MH, Elie N, Briand M, Vivien D, Poulain L, Gauduchon P, and N'Diaye M

Abstract

The anti-apoptotic proteins Bcl-x L and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-x L activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-x L strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-x L strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Published
2018
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25. Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies.

Author

Icard P, Zhang XD, Lemoisson E, Louis MH, Allouche S, Lincet H, and Poulain L

Subjects
Animals, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Female, Flow Cytometry, Humans, In Vitro Techniques, Mice, Mice, Nude, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2 metabolism, Apoptosis drug effects, Mesothelioma drug therapy, Metabolic Networks and Pathways physiology, Mitochondria drug effects, Models, Biological, Pyruvates pharmacology
Abstract

Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the "Warburg effect", to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.

Published
2012
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