Synergistic effects of HDAC inhibitor tucidinostat and ENT inhibitor dipyridamole in T-cell malignancies

Abstract Achieving both selectivity and cytotoxicity against cancer cells remains a major challenge in cancer therapy. Histone deacetylase (HDAC) inhibitors, such as tucidinostat, suppress tumor growth by epigenetically regulating tumor suppressor gene expression and are approved for the treatment of hematological malignancies. Despite their promising efficacy, frequent and severe adverse effects, particularly hematological toxicities, often limit long-term treatment, underscoring the urgent need for safer therapeutic strategies. In this study, we show ex vivo that combining tucidinostat with dipyridamole, an approved antiplatelet agent and equilibrative nucleoside transporter (ENT) inhibitor, reduces the effective dose of tucidinostat while maintaining its antitumor activity. In ex vivo models, this combination exerted specific and potent effects against T-cell lymphomas, including adult T-cell leukemia/lymphoma (ATL), inducing apoptosis beyond that achieved with either agent alone. Mechanistically, ENT inhibition appeared to enhance extracellular adenosine signaling, and activation of adenosine receptors, particularly A2b, contributed, at least in part, to the observed antitumor synergy. Moreover, tucidinostat-mediated HDAC inhibition was associated with upregulation of genes involved in adenosine signaling, including adenosine receptors as well as CD39 and CD73, suggesting a coordinated molecular mechanism underlying the enhanced efficacy. Collectively, these findings suggest that the combination of tucidinostat and dipyridamole may represent a promising therapeutic approach targeting both epigenetic and metabolic pathways to enhance cancer cell death in hematological malignancies.