Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines

Tiffany J. Somers-Edgar, Sebastien Taurin, Lesley Larsen, Anupama Chandramouli, Mark A Nelson, Rhonda J. Rosengren

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Summary: 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 EC50 values of 1.54 and 1.10 μM, respectively, in MDA-MB-231 cells and EC50 values of 0.51 and 0.23 in SKBr3 cells. All other new compounds examined were less potent than curcumin, which elicited EC50 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 G2/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.

Original languageEnglish (US)
Pages (from-to)87-97
Number of pages11
JournalInvestigational New Drugs
Volume29
Issue number1
DOIs
StatePublished - Feb 2011

Fingerprint

Curcumin
Estrogen Receptors
Breast Neoplasms
Cell Line
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 8
M Phase Cell Cycle Checkpoints
Glycogen Synthase Kinase 3
Catenins
Proteins
G2 Phase
cyclohexanone
Pharmaceutical Preparations
Apoptosis

Keywords

  • Apoptosis
  • Curcumin derivatives
  • Her-2
  • MDA-MB-231
  • SKBr3

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. / Somers-Edgar, Tiffany J.; Taurin, Sebastien; Larsen, Lesley; Chandramouli, Anupama; Nelson, Mark A; Rosengren, Rhonda J.

In: Investigational New Drugs, Vol. 29, No. 1, 02.2011, p. 87-97.

Research output: Contribution to journalArticle

Somers-Edgar, Tiffany J. ; Taurin, Sebastien ; Larsen, Lesley ; Chandramouli, Anupama ; Nelson, Mark A ; Rosengren, Rhonda J. / Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. In: Investigational New Drugs. 2011 ; Vol. 29, No. 1. pp. 87-97.
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AB - Summary: 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 EC50 values of 1.54 and 1.10 μM, respectively, in MDA-MB-231 cells and EC50 values of 0.51 and 0.23 in SKBr3 cells. All other new compounds examined were less potent than curcumin, which elicited EC50 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 G2/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.

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