Abstract
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.
Highlights
Cutaneous T-cell lymphomas (CTCLs) are rare skin malignancies, forming a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing mature T-cells [1]
We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDAC inhibitors (HDACi) resminostat in CTCL in vitro
We investigated for the first time the antitumor activity of JAK2 ruxolitinib and Histone Deacetylase (HDACs) inhibitor resminostat in the cytotoxicity, proliferation and apoptosis of CTCL cell lines, along with their impact in major cellular signaling pathways
Summary
Cutaneous T-cell lymphomas (CTCLs) are rare skin malignancies, forming a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing mature T-cells [1]. The fundamental difference in the putative cell of origin between SS (TCM-derived) and MF (TRM-derived) is consistent with their distinct clinical behaviors, since TCm may be found in all three compartments, i.e. in peripheral blood, lymph node and skin, while resident TRm-cells remain localized at the skin. Detection of these malignant T-cell clones is critical for the diagnosis of CTCL, with TCm expressing CCR7+/L-selectin+ and TRm expressing CCR7+/L-selectin- [11]. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro
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