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Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines
Investigational New Drugs, 10/13/09

Somers-Edgar TJ et al. – 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

Methods

Further modified cyclohexanone derivatives of curcumin and examined them for cytotoxicity towards ER-negative human breast cancer cells.
2 of analogs screened elicited increased cytotoxic potency compared to curcumin and other previously studied derivatives

Results

2 of 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 NF?B decreased in time-dependent manner, while activity of stress kinases JNK1/2 and P38 MAPK increased
Signaling events in MDA-MB-231 cells differently implicated, as EGFR protein levels decreased and activity of GSK-3? transiently decreased, while ?-catenin protein level and activity of P38 MAPK, Akt, and JNK1/2 transiently increased

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