Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma.
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Line, Tumor
Drug Synergism
Humans
Hydroxamic Acids
/ agonists
Lymphoma, T-Cell, Cutaneous
/ drug therapy
MAP Kinase Signaling System
/ drug effects
Neoplasm Proteins
/ metabolism
Nitriles
Pyrazoles
/ agonists
Pyrimidines
Sulfonamides
/ agonists
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
14
07
2020
accepted:
23
02
2021
entrez:
11
3
2021
pubmed:
12
3
2021
medline:
13
10
2021
Statut:
epublish
Résumé
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. 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. 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. The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.
Sections du résumé
BACKGROUND
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.
MATERIAL & METHODS
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.
RESULTS
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.
CONCLUSION
The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.
Identifiants
pubmed: 33705488
doi: 10.1371/journal.pone.0248298
pii: PONE-D-20-21841
pmc: PMC7951910
doi:
Substances chimiques
Hydroxamic Acids
0
Neoplasm Proteins
0
Nitriles
0
Pyrazoles
0
Pyrimidines
0
Sulfonamides
0
resminostat
1578EUB98L
ruxolitinib
82S8X8XX8H
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0248298Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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