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

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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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Acknowledgments

This work was supported by a grant from the Breast Cancer Research Trust (RJR) and a University of Otago Postgraduate Scholarship (TJS-E).

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, University of Otago, 18 Frederick Street, Adams Building, Dunedin, New Zealand

    Tiffany J. Somers-Edgar, Sebastien Taurin & Rhonda J. Rosengren

  2. New Zealand Institute for Plant and Food Research Ltd., Dunedin, New Zealand

    Lesley Larsen

  3. Department of Pathology, University of Arizona, Tucson, AZ, USA

    Anupama Chandramouli & Mark A. Nelson

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  1. Tiffany J. Somers-Edgar
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  2. Sebastien Taurin
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  6. Rhonda J. Rosengren
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Correspondence to Rhonda J. Rosengren.

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Somers-Edgar, T.J., Taurin, S., Larsen, L. et al. Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. Invest New Drugs 29, 87–97 (2011). https://doi.org/10.1007/s10637-009-9339-0

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