Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.

<h4>Background</h4>The combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro.&l...

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Autores principales:	Fani Karagianni, Christina Piperi, Vassiliki Mpakou, Aris Spathis, Periklis G Foukas, Maria Dalamaga, Vasiliki Pappa, Evangelia Papadavid
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0dc85252357a474f8d023cd0dc50c91a
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spelling	oai:doaj.org-article:0dc85252357a474f8d023cd0dc50c91a2021-12-02T20:04:09ZRuxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.1932-620310.1371/journal.pone.0248298https://doaj.org/article/0dc85252357a474f8d023cd0dc50c91a2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0248298https://doaj.org/toc/1932-6203<h4>Background</h4>The combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro.<h4>Material & methods</h4>Non-toxic concentrations of ruxolitinib and/or resminostat were administered to MyLa (MF) and SeAx (SS) cells for 24h. Cytotoxicity, cell proliferation and apoptosis were estimated through MTT, BrdU/7AAD and Annexin V/PI assay. Multi-pathway analysis was performed to investigate the effect of JAK1/2i and/or HDACi on JAK/STAT, Akt/mTOR and MAPK signalling pathways.<h4>Results</h4>Both drugs and their combination were cytotoxic in MyLa (p<0.05) and in SeAx cell line (p<0.001), inhibited proliferation of MyLa (p<0.001) and SeAx (p<0.001) at 24h, compared to untreated cells. Moreover, combined drug treatment induced apoptosis after 24h (p<0.001) in MyLa, and SeAx (p<0.001). The combination of drugs had a strong synergistic effect with a CI<1. Importantly, the drugs' combination inhibited phosphorylation of STAT3 (p<0.001), Akt (p<0.05), ERK1/2 (p<0.001) and JNK (p<0.001) in MyLa, while it reduced activation of Akt (p<0.05) and JNK (p<0.001) in SeAx.<h4>Conclusion</h4>The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.Fani KaragianniChristina PiperiVassiliki MpakouAris SpathisPeriklis G FoukasMaria DalamagaVasiliki PappaEvangelia PapadavidPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 3, p e0248298 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fani Karagianni Christina Piperi Vassiliki Mpakou Aris Spathis Periklis G Foukas Maria Dalamaga Vasiliki Pappa Evangelia Papadavid Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
description	<h4>Background</h4>The combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro.<h4>Material & methods</h4>Non-toxic concentrations of ruxolitinib and/or resminostat were administered to MyLa (MF) and SeAx (SS) cells for 24h. Cytotoxicity, cell proliferation and apoptosis were estimated through MTT, BrdU/7AAD and Annexin V/PI assay. Multi-pathway analysis was performed to investigate the effect of JAK1/2i and/or HDACi on JAK/STAT, Akt/mTOR and MAPK signalling pathways.<h4>Results</h4>Both drugs and their combination were cytotoxic in MyLa (p<0.05) and in SeAx cell line (p<0.001), inhibited proliferation of MyLa (p<0.001) and SeAx (p<0.001) at 24h, compared to untreated cells. Moreover, combined drug treatment induced apoptosis after 24h (p<0.001) in MyLa, and SeAx (p<0.001). The combination of drugs had a strong synergistic effect with a CI<1. Importantly, the drugs' combination inhibited phosphorylation of STAT3 (p<0.001), Akt (p<0.05), ERK1/2 (p<0.001) and JNK (p<0.001) in MyLa, while it reduced activation of Akt (p<0.05) and JNK (p<0.001) in SeAx.<h4>Conclusion</h4>The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.
format	article
author	Fani Karagianni Christina Piperi Vassiliki Mpakou Aris Spathis Periklis G Foukas Maria Dalamaga Vasiliki Pappa Evangelia Papadavid
author_facet	Fani Karagianni Christina Piperi Vassiliki Mpakou Aris Spathis Periklis G Foukas Maria Dalamaga Vasiliki Pappa Evangelia Papadavid
author_sort	Fani Karagianni
title	Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
title_short	Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
title_full	Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
title_fullStr	Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
title_full_unstemmed	Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
title_sort	ruxolitinib with resminostat exert synergistic antitumor effects in cutaneous t-cell lymphoma.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/0dc85252357a474f8d023cd0dc50c91a
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Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.

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