Targeting glioblastoma with HDAC inhibitors: insights into hydroxamic acid-based therapeutic strategies

Epigenetic modifications play crucial roles in glioblastoma growth and aggressiveness, with key regulators including histone deacetylases (HDACs), histone acetyltransferases (HATs), and methyltransferases. Targeting these epigenetic alterations has emerged as a promising therapeutic strategy, utilizing DNA methyltransferase (DNMT) inhibitors, HDAC inhibitors (HDACis), and miRNA-based therapies. HDACis, whose effect on p53, p21, Bax, and Bcl-2, have gained significant interest because of their ability to restore the expression of tumor suppressor genes, thereby inducing apoptosis and overcoming therapeutic resistance. Our study demonstrated that a novel hydroxamic acid analogue, compound 3B, effectively inhibited glioma cell (C6) proliferation and exhibited potent anticancer activity. Compound 3B induced G2/M phase cell cycle arrest, increased apoptotic cell populations, and significantly reduced colony formating efficiency. Confocal imaging revealed nuclear condensation and elevated reactive oxygen species (ROS) levels, indicating oxidative stress. Western blot analysis confirmed that HDAC inhibition increased AcH3K9 protein levels. Further, studies in in vivo xenograft model and allograft C6 Wistar rat model revealed strong antitumour activity, suggesting that compound 3B is a promising therapeutic candidate for glioblastoma treatment.