title: Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines.
abstract: Estrogen receptor (ER)-negative breast cancer is an aggressive form that currently requires more drug treatment options. Thus, we have further modified cyclohexanone derivatives of curcumin and examined them for cytotoxicity towards ER-negative human breast cancer cells. Two of the analogs screened elicited increased cytotoxic potency compared to curcumin and other previously studied derivatives. Specifically, 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91) elicited EC(50) values of 1.54 and 1.10 µM, respectively, in MDA-MB-231 cells and EC(50) values of 0.51 and 0.23 in SKBr3 cells. All other new compounds examined were less potent than curcumin, which elicited EC(50) values of 7.6 and 2.4 µM in MDA-MB-231 and SKBr3 cells, respectively. Mechanistic analyses demonstrated that RL90 and RL91 significantly induced G(2)/M-phase cell cycle arrest and apoptosis. RL90 and RL91 also modulated the expression of key cell signaling proteins, specifically, in SKBr3 cells, protein levels of Her-2, Akt, and NFκB were decreased in a time-dependent manner, while activity of stress kinases JNK1/2 and P38 MAPK were increased. Signaling events in MDA-MB-231 cells were differently implicated, as EGFR protein levels were decreased and activity of GSK-3β transiently decreased, while β-catenin protein level and activity of P38 MAPK, Akt, and JNK1/2 were transiently increased. In conclusion replacement of the phenyl group of cyclohexanone derived curcumin derivatives with heterocyclic rings forms a class of second-generation analogs that are more potent than both curcumin and other derivatives. These new derivatives provide a platform for the further development of drugs for the treatment of ER-negative breast cancer.
authors.affiliation: Department of Pharmacology & Toxicology, University of Otago, 18 Frederick Street, Adams Building, Dunedin, New Zealand.
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Somers-Edgar
authors.forename: Sebastien
authors.initials: S
authors.lastname: Taurin
authors.forename: Lesley
authors.initials: L
authors.lastname: Larsen
authors.forename: Anupama
authors.initials: A
authors.lastname: Chandramouli
authors.forename: Mark A
authors.initials: MA
authors.lastname: Nelson
authors.forename: Rhonda J
authors.initials: RJ
authors.lastname: Rosengren
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003512:Cyclohexanones; D006571:Heterocyclic Compounds; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; C036468:cyclohexanone; D003474:Curcumin