Targeting epigenetic and DNA topology mechanisms: histone deacetylases and topoisomerase inhibitors in combination and dual inhibition approaches

Cancer is a complex and multifactorial disease, often characterized by disruptions in key cellular processes such as gene expression and DNA topology. Histone deacetylases (HDACs) and topoisomerases (Topo) are two major molecular targets for cancer therapeutics due to their key role in maintaining DNA topology and contributing to cancer development. HDACs modify chromatin accessibility, while Topos resolve DNA supercoiling during replication. Targeting these pathways individually has shown therapeutic potential; however, recent advancements emphasize combination therapies and dual inhibitors as promising strategies to enhance anticancer efficacy. Combination therapies involving HDAC and Topo inhibitors leverage their complementary mechanisms of action to induce synergistic effects, leading to improved tumor suppression. Similarly, dual inhibitors, which integrate the functionalities of HDAC and Topo inhibitors into a single molecule, offer the potential to streamline treatment regimens, overcome drug resistance, and minimize adverse effects. This review provides a comprehensive overview of the therapeutic potential of HDAC-Topo combination therapies and dual inhibitors, emphasizing their mechanistic synergy, pharmacological benefits, and associated clinical challenges. It highlights the need for continued research to address limitations and improve their effectiveness and safety for broader applications in oncology.Clinical trial numberNot applicable.