PMID- 19816657
OWN - NLM
STAT- MEDLINE
DCOM- 20110411
LR  - 20211020
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 29
IP  - 1
DP  - 2011 Feb
TI  - Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in 
      estrogen receptor negative human breast cancer cell lines.
PG  - 87-97
LID - 10.1007/s10637-009-9339-0 [doi]
AB  - 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 microM, 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 microM 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 NFkappaB 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-3beta transiently decreased, 
      while beta-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.
FAU - Somers-Edgar, Tiffany J
AU  - Somers-Edgar TJ
AD  - Department of Pharmacology & Toxicology, University of Otago, 18 Frederick 
      Street, Adams Building, Dunedin, New Zealand.
FAU - Taurin, Sebastien
AU  - Taurin S
FAU - Larsen, Lesley
AU  - Larsen L
FAU - Chandramouli, Anupama
AU  - Chandramouli A
FAU - Nelson, Mark A
AU  - Nelson MA
FAU - Rosengren, Rhonda J
AU  - Rosengren RJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091009
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Cyclohexanones)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptors, Estrogen)
RN  - 5QOR3YM052 (cyclohexanone)
RN  - IT942ZTH98 (Curcumin)
SB  - IM
MH  - Breast Neoplasms/*pathology
MH  - Cell Death/drug effects
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Curcumin/*analogs & derivatives/chemistry/*pharmacology
MH  - Cyclohexanones/chemistry/*pharmacology
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - G2 Phase/drug effects
MH  - Heterocyclic Compounds/chemistry/*pharmacology
MH  - Humans
MH  - Neoplasm Proteins/metabolism
MH  - Receptors, Estrogen/*metabolism
MH  - Signal Transduction/drug effects
EDAT- 2009/10/10 06:00
MHDA- 2011/04/13 06:00
CRDT- 2009/10/10 06:00
PHST- 2009/08/27 00:00 [received]
PHST- 2009/09/28 00:00 [accepted]
PHST- 2009/10/10 06:00 [entrez]
PHST- 2009/10/10 06:00 [pubmed]
PHST- 2011/04/13 06:00 [medline]
AID - 10.1007/s10637-009-9339-0 [doi]
PST - ppublish
SO  - Invest New Drugs. 2011 Feb;29(1):87-97. doi: 10.1007/s10637-009-9339-0. Epub 2009 
      Oct 9.