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Enhanced suppression of proliferation and migration in highly-metastatic lung cancer cells by combination of valproic acid and coumarin-3-carboxylic acid and its molecular mechanisms of action

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Abstract

Valproic acid (VPA) as a broad-spectrum inhibitor of histone deacetylase, has been used in cancer therapy. Recently, the combination of VPA with other anticancer agents has been considered as a useful and necessary strategy to inhibit tumor growth and progression. The coumarin derivates from natural plants have been shown to be the promising natural anticancer agents. However, no literature is available on the anticancer effects of the combination of VPA and coumarin-3-carboxylic acid (HCCA). Here we show that this combination significantly increases inhibitory effects against the proliferation and migration in highly-metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions. Our results indicate that this combination of VPA with HCCA not only enhances the protein levels of Bax, cytosolic cytochrome c, caspase-3 and PARP-1 but also reduces the protein expressions of Bcl-2, cyclin D1 and NF-κB as well as inhibits the phosphorylation and expressions of Akt, EGFR, VEGFR2 and c-Met in the cancer cells. Our results suggest that the combination of VPA with HCCA suppresses the proliferation and migration of lung cancer cells via EGFR/VEGFR2/c-Met-Akt-NF-κB signaling pathways; this combination may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of lung cancer.

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Abbreviations

VPA:

Valproic acid

HCCA:

Coumarin-3-carboxylic acid

NF-κB:

Nuclear factor κB

VEGFR2:

Vascular endothelial growth factor receptor-2

EGFR:

Epidermal growth factor receptor

Ly:

Ly294002

Bay:

Bay 11-7082

PARP:

Poly(ADP-ribose) polymerase

Cyto C:

Cytochrome c

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

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Acknowledgments

This work is supported in part by grant (863) from the Ministry of Science and Technology of the People’s Republic of China to G.Z (2012AA020206), from the Ministry of Human Resources and Social Security of the People’s Republic of China to G.Z, Projects of Yantai University to GZ, Project from the National Natural Science Foundation of China to GZ (No. 30973553), and grants from the Department of Science and Technology of Shandong Province to GZ (ZR2012HM016; 2009GG10002087).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, No. 30, Qing Quan Lu, Lai Shan Qu, Yantai, Shandong Province, 264005, China

    Xin Liu, Linlin Chen, Fujia Sun & Guoying Zhang

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  1. Xin Liu
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  2. Linlin Chen
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  3. Fujia Sun
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  4. Guoying Zhang
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Correspondence to Guoying Zhang.

Additional information

Xin Liu, Linlin Chen and Fujia Sun contributed equally to this work.

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Liu, X., Chen, L., Sun, F. et al. Enhanced suppression of proliferation and migration in highly-metastatic lung cancer cells by combination of valproic acid and coumarin-3-carboxylic acid and its molecular mechanisms of action. Cytotechnology 65, 597–608 (2013). https://doi.org/10.1007/s10616-012-9513-7

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  • DOI: https://doi.org/10.1007/s10616-012-9513-7

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