Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and a leading cause of cancer worldwide. Histone deacetylases (HDACs), which regulate cell proliferation and survival, are associated with the development and progression of cancer. Moreover, HDAC inhibitors are promising therapeutic targets, with five HDAC inhibitors approved for cancer treatment to date. However, their safety profile necessitates the exploration of well-tolerated HDAC inhibitors that can be used in cancer therapeutic strategies. In this study, the pan-HDAC inhibitor MPT0G236 reduced the viability and inhibited the proliferation of human colorectal cancer cells, and normal human umbilical vein endothelial cells (HUVECs) showed reduced sensitivity. These findings indicated that MPT0G236 specifically targeted malignant tumor cells. Notably, MPT0G236 significantly inhibited the activities of HDAC1, HDAC2, and HDAC3, Class I HDACs, as well as HDAC6, a Class IIb HDAC, at low nanomolar concentrations. Additionally, it promoted the accumulation of acetyl-α-tubulin and acetyl-histone H3 in HCT-116 and HT-29 cells in a concentration-dependent manner. Furthermore, MPT0G236 treatment induced G2/M cell cycle arrest in CRC cells by initially regulating the levels of cell-cycle-related proteins, such as p-MPM2; specifically reducing p-cdc2 (Y15), cyclin B1, and cdc25C levels; and subsequently inducing apoptosis through the caspase-dependent pathways and PARP activation. Our findings demonstrate that MPT0G236 exhibits significant anticancer activity in human colorectal cancer cells.

A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC₅₀ values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC₅₀ values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase. Graphical Abstract

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.

This study investigated the incorporation of C5, a pan-HDAC inhibitor, into a norbornene-derived block copolymer with pH-sensitive hydrolysis (PNEG-b-P(Nor-PABA-C5)) to generate NPs for prostate cancer treatment. Amphiphilic PNEG-b-P(Nor-PABA-C5) formed NPs in aqueous environments, with hydrophobic Nor-PABA-C5 monomers in the core and hydrophilic PNEG monomers on the surface. DLS analysis showed a particle size of 122 ± 12 nm with a PDI of 0.35, confirmed by SEM and TEM. TEM imaging revealed spherical morphology, enabling the NPs to transport hydrophobic pan-HDACi drugs to PC-3 tumour sites and facilitate release through hydrolysis under acidic conditions. The NPs exhibited pH-hydrolysis characteristics, with enhanced drug release (61 ± 1.7%) at pH 6.2 compared to pH 7.4 (35 ± 0.8%). MTT assay confirmed antiproliferative effect. Analysis of FITC/(PNEG-b-P(Nor-PABA-C5)) cellular uptake showed increased absorption in prostate tumours. Live/dead cell assays showed loss of viability, with increased red fluorescence and morphological disruption at higher concentrations over 48 and 72 h.