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

Abstract

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.

• Authors: Fani Karagianni, Christina Piperi, Vassiliki Mpakou, Aris Spathis, Periklis G Foukas, Maria Dalamaga, Vasiliki Pappa, Evangelia Papadavid
• Journal: PloS one (PLoS One) Vol. 16 Issue 3 Pg. e0248298 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 33705488 (Publication Type: Journal Article)

Chemical References

• Hydroxamic Acids
• Neoplasm Proteins
• Nitriles
• Pyrazoles
• Pyrimidines
• Sulfonamides
• resminostat
• ruxolitinib

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Drug Synergism
• Humans
• Hydroxamic Acids (agonists, pharmacology)
• Lymphoma, T-Cell, Cutaneous (drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Neoplasm Proteins (metabolism)
• Nitriles
• Pyrazoles (agonists, pharmacology)
• Pyrimidines
• Sulfonamides (agonists, pharmacology)