title: Benzylidenetetralones, cyclic chalcone analogues, induce cell cycle arrest and apoptosis in HCT116 colorectal cancer cells.
abstract: Colorectal cancer is the third most common cancer in the world, with 1.2 million new cancer cases annually. Chalcones are secondary metabolite precursors of flavonoids that exhibit diverse biological activities, including antioxidant and antitumor activities. The aim of this study was to investigate the antiproliferative effect of new synthetic chalcone derivatives on HCT116 cells. (E)-2-(2',4'-dimethoxybenzylidene)-1-tetralone (Q705) was found to be the most active (IC50 = 3.44 ± 0.25 μM). Based on these results, this compound was chosen for further analysis of its biochemical and molecular mechanisms. Our results showed that Q705 inhibited the growth and clonogenicity of HCT116 cells. The results of a flow cytometric analyses suggested that this compound caused a significant cell cycle arrest in G2/M phase and increased the proportion of cells in the subG0/G1 phase, marker of apoptosis. Q705-induced apoptosis was confirmed by TdT-mediated dUTP nick end labelling (TUNEL) assay. Treatment of HCT116 cells with this chalcone significantly increased the caspase-3,-7 activity and resulted in cleavage of poly-ADP-ribose polymerase (PARP). Changes in the nuclear morphology such as chromatin condensation were also observed. These effects were associated with a decreased expression of bcl-xL and increased overall ratio of bax/bcl-xL mRNA levels. Immunofluorescence and qRT-PCR analysis revealed that Q705 induced H2AX histone modifications characteristic of DNA damage, disruption of microtubule organization and downregulation of tubulins. In summary, these results suggest that the cyclic chalcone analogue Q705 has potential as a new compound for colorectal cancer therapy.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovak Republic.
authors.forename: David
authors.initials: D
authors.lastname: Drutovic
authors.forename: Martina
authors.initials: M
authors.lastname: Chripkova
authors.forename: Martina
authors.initials: M
authors.lastname: Pilatova
authors.forename: Peter
authors.initials: P
authors.lastname: Kruzliak
authors.forename: Pal
authors.initials: P
authors.lastname: Perjesi
authors.forename: Marek
authors.initials: M
authors.lastname: Sarissky
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Jan
authors.initials: J
authors.lastname: Mojzis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D047188:Chalcones