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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

LFM-A13, a Potent Inhibitor of Polo-Like Kinase, Inhibits Breast Carcinogenesis by Suppressing Proliferation Activity and Inducing Apoptosis in Breast Tumors of Mice

Kazim Sahin, Mehmet Tuzcu, Mehmet Yabas, Cemal Orhan, Nurhan Sahin, Ibrahim H Ozercan

Invest New Drugs. 2018 Jun;36(3):388-395.

PMID: 29139009

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP244240242	LFM-A13		244240-24-2	Price

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