title: Chalcone-imidazolone conjugates induce apoptosis through DNA damage pathway by affecting telomeres.
abstract: BACKGROUND
  Breast cancer is one of the most prevalent cancers in the world and more than one million women are diagnosed leading to 410,000 deaths every year. In our previous studies new chalcone-imidazolone conjugates were prepared and evaluated for their anticancer activity in a panel of 53 human tumor cell lines and the lead compounds identified were 6 and 8. This prompted us to investigate the mechanism of apoptotic event.
  
  
  RESULTS
  Involvement of pro-apoptotic protein (Bax), active caspase-9 and cleavage of retinoblastoma protein was studied. Interestingly, the compounds caused upregulation of p21, check point proteins (Chk1, Chk2) and as well as their phosphorylated forms which are known to regulate the DNA damage pathway. Increased p53BP1 foci by immunolocalisation studies and TRF1 suggested the possible involvement of telomere and associated proteins in the apoptotic event. The telomeric protein such as TRF2 which is an important target for anticancer therapy against human breast cancer was extensively studied along with proteins involved in proper functioning of telomeres.
  
  
  CONCLUSIONS
  The apoptotic proteins such as Bax, active caspase-9 and cleaved RB are up-regulated in the compound treated cells revealing the apoptotic nature of the compounds. Down regulation of TRF2 and upregulation of the TRF1 as well as telomerase assay indicated the decrease in telomeric length revealing telomeric dysfunction and thereby controlling the rapid rate of cell proliferation. In summary, chalcone-imidazolone conjugates displayed significant DNA damage activity particularly at telomeres and caused both apoptosis and senescence-like growth arrest which suggested that these compounds have potential activity against breast carcinoma.
authors.affiliation: Division of Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.affiliation: Division of Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: Sncvl
authors.initials: S
authors.lastname: Pushpavalli
authors.affiliation: Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: G Rama
authors.initials: GR
authors.lastname: Krishna
authors.affiliation: Division of Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: Pranjal
authors.initials: P
authors.lastname: Sarma
authors.affiliation: Division of Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: Debasmita
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Division of Functional Genomics and Gene silencing, Centre for Cellular and Molecular Biology, Tarnaka, Hyderabad-500007, India.
authors.forename: Utpal
authors.initials: U
authors.lastname: Bhadra
authors.affiliation: Division of Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500607, India.
authors.forename: Manika Pal
authors.initials: MP
authors.lastname: Bhadra