Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of Histone Deacetylases (HDAC)

Abstract

Recent studies from our group and many others have shown the ability of histone deacetylase (HDAC) inhibitors for retarding the growth of carcinomas of cervix, colon and rectum in vitro. A search for naturally occurring HDAC inhibitors continues due to the adverse effects associated with known HDAC inhibitors like SAHA and TSA. Therefore in the current study, naturally occurring cinnamic acids derivatives were screened for HDAC inhibitory effect using in silico docking method which identified cinnamic acids as potential candidates. Cinnamic acids (CA) are naturally occurring phenolic compounds known to exhibit anticancer properties. However, it is not clearly known whether the anticancer properties of CA derivatives are due to the inhibition of oncogenic HDACs, if so how the efficacy varies among various CA derivatives. Hence, the HDAC inhibitory potential of CA derivatives containing increasing number of hydroxylic groups or methoxy moieties was determined using Discovery Studio software and the most potent CA derivatives tested ex vivo (biochemical assay) as well as in vitro (using cell based assay). Among CA derivatives tested, dihydroxy cinnamic acid (DHCA, commonly known as caffeic acid) exhibited better interactions with HDAC2 (compared to other isoforms) in silico and inhibited its activity ex vivo as well as in vitro. Targeted reduction of HDAC activity using DHCA induced death of cancer cells by (a) generating reactive oxygen species, (b) arresting cells in S and G2/M phases; and (c) induction of caspase-3 mediated apoptosis. In conclusion, we demonstrated that DHCA inhibited cancer cell growth by binding to HDAC followed by the induction of apoptosis.

Epigenetic Inactivation of Acetyl-Co A acetyltransferase 1 promotes the proliferation and metastasis of nasopharyngeal carcinoma via decreasing ketogenesis

“…We observed increased acetylation of lysine 9 and lysine 14 of histone 3 in the promoter region of CDH1 after the treatment with β-HB, indicating transcriptional stimulation of CDH1 (data not shown). HDACi induced p53-dependent apoptosis in NPC cells (30) and retarded the growth of carcinomas of the cervix, colon, and rectum in vitro (31). Surprisingly, a recent study reported that NPC cells were turned into a mesenchymal cell phenotype after short-term stimulation with the HDACi trichostatin A.…”

Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

“…The widely reported anticancer potential of many natural or synthetic CAD [9,10,13,[33][34][35][36][37][38][39], and the antiproliferative properties of known antimalarial drugs, like chloroquine (2) [69] or quinacrine (4) [70,71], motivated the investigation of CA-antimalarial drug conjugates as anticancer leads. Hence, Pérez et al have investigated the antiproliferative activity of compounds 8 (Figure 2) on MKN-28 (gastric cancer), Caco-2 (colorectal adenocarcinoma), and MFC-7 (breast cancer) cell lines; all compounds were active in the micromolar range, while being non-toxic to the normal HFF-1 (human foreskin fibroblast) cell line.…”

“…Depending on their therapeutic targets, different modes of action seem to be exerted by CA and their derivatives or analogues. For instance, interactions with pathogens' membranes have been associated with the antimicrobial action of CA [30][31][32], whereas anticancer properties of different CA have been related to apoptosis [33][34][35][36][37][38][39], which encompasses various events including "S"-cycle arrest [34], cytoskeleton disruption [37], activation of caspases [38], generation of reactive oxygen species (ROS) [35,36], and inhibition of histone deacetylases [33,39].…”

PON1 hypermethylation is associated with progression of renal cell carcinoma

“…Yan et al also used 5‐Aza‐dC, which was down‐regulated the DNA methylation of SPARC , to study the progression of T‐cell lymphoma . As a kind of histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) could retard the growth of carcinomas of cervix, colon, rectum and other cancers in vitro . What's more, the co‐treatment of 5‐Aza‐dC and TSA showed a better effect in human gastric cancer cells .…”

“…22 As a kind of histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) could retard the growth of carcinomas of cervix, colon, rectum and other cancers in vitro. 23 What's more, the co-treatment of 5-Aza-dC and TSA showed a better effect in human gastric cancer cells. 24 In addition, sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), which currently was the standard of care for patients suffering from metastatic renal cell cancer.…”