Synergistic Efficacy of Chidamide and <scp>LB100</scp> in Sézary Syndrome via <scp>TNC</scp> Downregulation and <scp>PI3K</scp> / <scp>AKT</scp> / <scp>mTOR</scp> Dephosphorylation

Primary cutaneous T-cell lymphoma (CTCL) manifests as a distinct variant of T-cell non-Hodgkin's lymphoma, predominantly impacting skin tissues and constituting approximately 75%-80% of cutaneous lymphoma cases, exhibiting diverse clinical presentations. Sezary syndrome (SS) is a rare subtype of CTCL. The therapeutic approach of SS frequently incorporates multiple chemotherapeutic compounds, encompassing specific histone deacetylase inhibitor agents. Nevertheless, similar to numerous chemotherapeutic protocols, existing monotherapy approaches for SS encounter limitations regarding sustained therapeutic outcomes and optimal effectiveness. This investigation seeks to examine the therapeutic impact and molecular pathways of combining Chidamide with LB100 in the treatment of SS. The synergistic effects of Chidamide and LB100 were evaluated in SS cell lines (Hut78 and H9) using the Cell Counting Kit-8, Chou-Talalay combination index, colony formation assays, and mouse xenograft models. Apoptosis was examined by Annexin V-APC/PI staining. The molecular mechanisms were explored through transcriptome sequencing, Western blotting, immunohistochemistry, and Lentivirus transfection. Chidamide and LB100 demonstrated synergistic antitumor activity in SS cell lines (Hut78 and H9) in vitro, with a combination index (CI) < 1. This synergy was also confirmed in Hut78 xenograft mice. Mechanistically, the two agents downregulated Tenascin C (TNC) and caused dephosphorylation of the PI3K/AKT/mTOR signaling cascade. This study also preliminarily validated the effect of the combination of the two drugs on other subtypes of CTCL. Overall, these findings provide potential new therapeutic strategies for CTCL (especially SS), although further clinical evaluation is required to validate these results.