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

PLoS One. 2017 Nov 30;12(11):e0186208. doi: 10.1371/journal.pone.0186208. eCollection 2017.


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.

MeSH terms

  • Apoptosis / drug effects*
  • Binding Sites
  • Butyric Acid / pharmacology
  • Cell Line, Tumor
  • Cinnamates / chemistry
  • Cinnamates / metabolism
  • Cinnamates / pharmacology*
  • Colorectal Neoplasms / pathology*
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / metabolism
  • Uterine Cervical Neoplasms / pathology*


  • Cinnamates
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Butyric Acid
  • cinnamic acid
  • trichostatin A

Grant support

PGA would like to acknowledge University Grants Commission, Government of India for providing Maulana Azad National Fellowship (F117.1/201415/MANF201415JAIKAR3409). PGA also would like to acknowledge Department of Science and Technology (DST)-Fund for the Improvement of Science and Technology infrastructure (FIST) supported Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) laboratory, Department of Biochemistry, JSS Medical College, JSS University for allowing me to carry out research studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.