Evaluation of Novel 3-Hydroxyflavone Analogues as HDAC Inhibitors against Colorectal Cancer

Abstract EN

Alteration of epigenetic enzymes is associated with the pathophysiology of colon cancer with an overexpression of histone deacetylase 8 (HDAC8) enzyme in this tissue.

Numerous reports suggest that targeting HDAC8 is a viable strategy for developing new anticancer drugs.

Flavonols provide a rich source of molecules that are effective against cancer; however, their clinical use is limited.

The present study investigated the potential of quercetin and synthetic 3-hydroxyflavone analogues to inhibit HDAC8 enzyme and evaluated their anticancer property.

Synthesis of the analogues was carried out, and cytotoxicity was determined using MTT assay.

Nonspecific and specific HDAC enzyme inhibition assays were performed followed by the expression studies of target proteins.

Induction of apoptosis was studied through annexin V and caspase 3/7 activation assay.

Furthermore, the analogues were assessed against in vivo colorectal cancer.

Among the synthesized analogues, QMJ-2 and QMJ-5 were cytotoxic against HCT116 cells with an IC50 value of 68 ± 2.3 and 27.4 ± 1.8 µM, respectively.

They inhibited HDAC enzyme in HCT116 cells at an IC50 value of 181.7 ± 22.04 and 70.2 ± 4.3 µM, respectively, and inhibited human HDAC8 and 1 enzyme at an IC50 value of <50 µM with QMJ-5 having greater specificity towards HDAC8.

A reduction in the expression of HDAC8 and an increase in acetyl H3K9 expression were observed with the synthesized analogues.

Both QMJ-2 and QMJ-5 treatment induced apoptosis through the activation of caspase 3/7 evident from 55.70% and 83.55% apoptotic cells, respectively.

In vivo studies revealed a significant decrease in colon weight to length ratio in QMJ-2 and QMJ-5 treatment groups compared to DMH control.

Furthermore, a reduction in aberrant crypt foci formation was observed in the treatment groups.

The present study demonstrated the potential of novel 3-hydroxyflavone analogues as HDAC8 inhibitors with anticancer property against colorectal cancer.