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

Shun-Lai Li; Chia-Hsin Huang; Chih-Chan Lin; Zih-Ning Huang; Jyh-Haur Chern; Hsiao-Yin Lien; Yong-Yi Wu; Chia-Hui Cheng; Chia-Yu Chang; Jiunn-Jye Chuu

doi:10.1007/s10637-009-9337-2

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

Journal

Investigational New Drugs

Journal Volume

29

Journal Issue

2

Pages

195-206

Date Issued

2011-04

Date

2011-04

Author(s)

Shun-Lai Li

Chia-Hsin Huang

Chih-Chan Lin

Zih-Ning Huang

Jyh-Haur Chern

Hsiao-Yin Lien

Yong-Yi Wu

Chia-Hui Cheng

Chia-Yu Chang

Jiunn-Jye Chuu

DOI

10.1007/s10637-009-9337-2

URI

https://scholars.tari.gov.tw/handle/123456789/14331

https://link.springer.com/article/10.1007%2Fs10637-009-9337-2

Abstract

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 mu M 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.

Subjects

Cyanoguanidine

Lung cancer

Histoculture

Nude mouse model

MDR-1 gene

Publisher

Kluwer Academic Publishers

Type

journal article

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