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LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice

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Summary

The goals of the present study were to define the anticancer activity of LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM-A13 would improve the efficiency of paclitaxel in breast cancer growth in vivo. To do this, female BALB/c mice received 1 mg of DMBA once a week for 6 weeks with oral gavage. LFM-A13 (50 mg/kg body weight) was administered intraperitoneally with DMBA administration and continued for 25 weeks. We found that LFM-A13, paclitaxel, and their combination have a significant effect on the DMBA-induced breast tumor incidence, mean tumor numbers, average tumor weight, and size. At the molecular level, the administration of LFM-A13 hindered mammary gland carcinoma development by regulating the expression of PLK1, cell cycle-regulating proteins cyclin D1, cyclin dependent kinase-4 (CDK-4), and the CDK inhibitor, p21. Moreover, LFM-A13 treatment upregulated the levels of IκB, the pro-apoptotic proteins Bax, and caspase-3, and down-regulated p53 and the antiapoptotic protein Bcl-2 in mammary tumors. The combination of LFM-A13 with paclitaxel was found to be more effective compared with either agent alone. Collectively, these results suggest that LFM-A13 has an anti-proliferative activity against breast cancer in vivo and that LFM-A13 and paclitaxel combination could be a strategy for the treatment of breast cancer.

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Acknowledgements

The authors thank Prof. Fatih Uckun (USC-USA) for kindly providing LFM-A13, and Prof. Gerard F. Hoyne (The University of Notre Dame Australia) for carefully reading and correcting grammar of the manuscript. The work was supported in part by the Turkish Academy of Sciences.

Funding

The work was supported in part by the Turkish Academy of Sciences.

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Authors and Affiliations

  1. Faculty of Veterinary Medicine, Firat University, Elazig, Turkey

    Kazim Sahin, Cemal Orhan & Nurhan Sahin

  2. Department of Biology, Faculty of Science, Firat University, Elazig, Turkey

    Mehmet Tuzcu

  3. Department of Genetics and Bioengineering, Trakya University, Edirne, Turkey

    Mehmet Yabas

  4. Department of Pathology, Faculty of Medicine, Firat University, Elazig, Turkey

    Ibrahim H. Ozercan

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Correspondence to Kazim Sahin.

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Sahin, K., Tuzcu, M., Yabas, M. et al. LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice. Invest New Drugs 36, 388–395 (2018). https://doi.org/10.1007/s10637-017-0540-2

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