(The) novel histone deacetylase inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide, shows potent antitumor activity due to cytoplasmic free calcium mediated apoptosis in thyroid cancer both in vitro and in vivo

Abstract

Epigenetic changes play a crucial role in the regulation of all DNA-based processes, such as transcription, repair, and replication. Improper histone changes can consequence in dysregulation of cell growth, leading to tumorigenic transformation and cell death. Thyroid cancer has been shown to have a higher global methylation percentage and reduced histone acetylation. Preclinical models have showed that histone gene modifiers and epigenetic changes play significant roles in papillary (PTC) and anaplastic (ATC) thyroid cancer tumorigenesis. These days, a novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), has been introduced therapeutic approaches to thyroid cancer as an example of a new class of anti-cancer agents. Here, we prove the ER stress (Endoplasmic Reticulum)-dependent apoptosis inducing activity of HNHA in cultured patient-derived thyroid cancer cells. Apoptosis in the HNHA-treated group was induced significantly, with marked caspase activation and Bcl-2 suppression in thyroid cells in vitro and in vivo. HNHA treatment caused cytoplasmic free calcium release from ER. HNHA also induced ER stress-dependent apoptosis, suggesting that HNHA can induce caspase-independent nuclear apoptosis in PTC and ATC. An in vivo study showed that HNHA had greater anti-tumor and pro-apoptotic effects on PTC and ATC xenografts than the established HDAC inhibitors. In conclusion, HNHA has more potent anti-tumor activity than established HDAC inhibitors and its activities are mediated by caspase-dependent and ER stress-mediated apoptosis in thyroid cancer cells. These results suggest that HNHA may offer a new therapeutic approach to thyroid cancer