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Antitumor effect of BPR-DC-2, a novel synthetic cyclic cyanoguanidine derivative, involving the inhibition of MDR-1 expression and down-regulation of p-AKT and PARP-1 in lung cancer

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In our previous study, a series of novel cyclic cyanoguanidine compounds, eg. 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4- pyrimidinone derivatives have been successfully synthesized and showed remarkable cytotoxicity in several cancer cell lines. In this present study, it is our aim to screen more potential candidates among the cyclic pyridyl cyanoguanidine compounds (BPR-DC-1, 2, 3) by in vitro and in vivo studies for the therapy of lung cancer, alternatively. Our results showed that BPR-DC-2 significantly inhibited proliferation of tumor cells with an IC50 of 3.60 ± 1.27 and 14.81 ± 4.23 μM in human lung carcinoma cells, H69 and A549, respectively by the MTT assay at 48 hr; BPR-DC-2 also obviously suppressed the tumor proliferation and MDR-1 gene expression, even induced cell apoptosis in the ex vivo histocultured lung tumor. We further demonstrated that, in the nude mouse model of metastatic lung cancer, BPR-DC-2 could diminish the tumor mass, retard the progression of metastasis, and prolong the survival time. In addition, it was found that BPR-DC-2 exerted its anti-tumor effects through the inhibition of MDR-1 gene expression and down-regulation of tumor anti-apoptosis signals (activated p-AKT and over-expression of PARP-1) by western blotting analysis. In conclusion, in this present study we have demonstrated that BPR-DC-2, derived from a series of novel synthetic cyclic cyanoguanidine compounds, has proved its potential as an anti-tumor drug candidate in treating lung cancer.

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Acknowledgments

The investigation was partially supported by a research grant (CCMP96-RD-015) Committee on Chinese pharmacy, department of health, executive Yuan, Taipei, Taiwan. Meanwhile, and by the National Science council, the Republic of China, under grant (NSC 94-2320-B-218 -001).

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Authors and Affiliations

  1. Institute of Biotechnology, College of Engineering, Southern Taiwan University, No.1, Nantai St, Yung-Kang City, Tainan county, 710, Taiwan

    Shun-Lai Li, Zih-Ning Huang, Yong-Yi Wu, Chia-Hui Cheng, Chia-Yu Chang & Jiunn-Jye Chuu

  2. Institute of Biomedical Engineering, College of Engineering, National Cheng Kung University, No.1, University Road, Tainan City, 701, Taiwan

    Chia-Hsin Huang

  3. Agricultural Research Institute, Council of Agriculture Executive, Yuan, No.189, Jhongjheng Rd., Wufong Country, Taichung county, 413, Taiwan

    Chia-Hsin Huang

  4. Department of Medical Research, Chi-Mei Medical Center, No. 901, Zhong Hua Rd, Yong Kang City, Tainan county, 710, Taiwan

    Chih-Chan Lin & Chia-Yu Chang

  5. Department of Veterinary Medicine, National Chung Hsing University, No. 250, Kuo Kuang Rd., Taichung City, 402, Taiwan

    Chih-Chan Lin

  6. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Township, Miaoli county, 350, Taiwan

    Jyh-Haur Chern

  7. Department of Pharmacy, Yongkang Veterans Hospital, No.427, Fuxing Rd., Yung-Kang City, Tainan County, 710, Taiwan

    Hsiao-Yin Lien

  8. Department of Pharmacy, Wei Gong Memorial Hospital, No. 128, Sinyi Rd, Toufen Township, Miaoli County, 351, Taiwan

    Jiunn-Jye Chuu

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  1. Shun-Lai Li
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Correspondence to Chia-Yu Chang or Jiunn-Jye Chuu.

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Li, SL., Huang, CH., Lin, CC. et al. Antitumor effect of BPR-DC-2, a novel synthetic cyclic cyanoguanidine derivative, involving the inhibition of MDR-1 expression and down-regulation of p-AKT and PARP-1 in lung cancer. Invest New Drugs 29, 195–206 (2011). https://doi.org/10.1007/s10637-009-9337-2

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