Anti-cancer mechanism of chidamide

Chidamide is a benzamide based histone deacetylase inhibitor (HDACi). Under physiological concentration in patients, it exerts significant inhibition on the enzymatic activities of HDAC subtypes 1, 2, 3, and 10, but not on the activities of other subtypes.

Chidamide (CS055) targets the narrow portion on top of the active pocket of HDAC, rather than direct chelation with the zinc ion in the catalytic site, whereas the hydroxamic acid (TSA) inhibitors directly chelate with zinc ion in the catalytic site. With types of inhibitor such as chidamide, although they are located close to the active center and work slowly, once they are close, they do not easily detach; therefore, the interaction lasts for a long time, which is opposite to hydroxamic acid inhibitors.

Xie EH et al.,Curr Med Chem Anticancer Agents.2004;4(3):273-99
Ning ZQ et al.,Cancer Chemother Pharmacol.,2012;69(4):901-909
Dong M et al.,Cancer Chemother Pharmacol.,2012;69(6):1413-22
Bantscheff M. et al.,Nature Biotechnology,2011;29(3):255-265

Figure 1. Diagram showing the binding of chidamide to the catalytic center of HDAC.

Studies have shown that chidamide exerts its anti-cancer effects through various mechanisms, including inhibition of the cancer cell cycle, induction of cancer cell differentiation and apoptosis, regulation of anti-cancer immunity, and inhibition of drug resistance-related tumor cell transformation.

Figure 2. Possible anti-cancer mechanism of chidamide

1. Through the selective inhibition of the activity of specific HDAC subtypes, chidamide can promote the acetylation of histones in target gene promoter regions and the binding of transcription complexes and, on the other hand, by non-histone-acetylation, alter protein activity and cellular localization (cytoplasmic/nuclear translocation) and further influence specific chromatin regions and the transcriptional activity of the corresponding target genes.
2. Through the regulation of cell cycle protein expression in cancer cells, the induction of ROS formation, and the inhibition of DNA damage repair, chidamide can inhibit the cancer cell cycle, and induce cancer cell differentiation and apoptosis.
3. Through the induction of the expression of specific tumor cell surface antigen and co-stimulatory molecules, chidamide enhances cytotoxic T lymphocyte (CTL)-mediated anti-cancer immunity, induces the expression of MHC-1 antigens on cancer cell surface and activation-related markers in NK cells and thereby enhances NK cell-mediated immunity. Meanwhile, chidamide can reduce the chronic inflammatory response in the local tumor tissues through the inhibition of inflammation factors in signaling pathways.
4. Through the inhibition of the epithelial-mesenchymal transition (EMT), the regulation of cancer stem cell activity, the improvement of cancer stem cell differentiation, and the sensitivity to other therapies, chidamide reduces the risk of tumor metastasis and recurrence.

Through the above described multiple interacting mechanisms, chidamide inhibits tumor growth and reduces the risk of tumor metastasis and recurrence. These mechanisms not only support the single drug efficacy of chidamide in T lymphoma treatment, but also provide scientific support for the long-term clinical benefits of the combination of chidamide with other therapies specifically for different types of cancers.