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

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 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.

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

“…This phenomenon could further support the hypothesis that MDR reversal caused by P110-knockout may not be dependent on AKT expression levels. As some researchers have previously suggested, AKT activated by PI3K might be associated with the MDR of cancer cells [30,31]. Our studies proposed that the AKT-mediated MDR-enhancing pathway might be independent of the regulation of ABC transporter-mediated MDR and may be activated during crisis conditions, such as when the ABC transporters fail to efficiently pump toxins out of the cells.…”

Synthesis and Biological Evaluation of Some New Ferrocenyl Phenyl Guanidines as Antibacterial, Antifungal Agents

“…Many natural occurring metabolites found in varieties of organisms contain guanidine moiety [3]. They have immense applications, especially in the field of medicines as neurotransmitter [6], cardiovascular, antihypertensive drugs [7], antibiotics [8,9], cytotoxic agents [10] and as an inhibitor of urokinase, responsible for a large number of malignancies including breast, lung, bladder, stomach, cervix, kidney and brain cancers [11][12][13]. On the other hand, ferrocene is one of the most favored building blocks in the construction of sensing platforms based on redox-active units due to the availability, stability and tailor ability of most of its derivatives [14][15][16].…”