title: A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome.
abstract: Chalcones and their derivatives have been shown to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 microM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It is noteworthy that AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell-killing activity of IR in both wild-type p53 and p53-null cells. Together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.
authors.affiliation: Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Geetha
authors.initials: G
authors.lastname: Achanta
authors.forename: Aneta
authors.initials: A
authors.lastname: Modzelewska
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C512278:3,5-bis(4-boronic acid-benzylidene)-1-methylpiperidin-4-one; D000970:Antineoplastic Agents; D001896:Boron Compounds; D001897:Boronic Acids; D047188:Chalcones; D010880:Piperidines; D061988:Proteasome Inhibitors; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex