Investigation of antitumor mechanism of the chiral ruthenium complex Lambda-[Ru(phen)(2)p-MOPIP](2+) in human gastric cancer MGC-803 cells

摘要

There has been a vast increase in telomerase inhibition research over the past several years, which was demonstrated as an attractive anti-tumor strategy. Our previous study found that the chiral ruthenium complex, [Ru(phen)(2)p-MOPIP](2+) (Phen = 1,10-phenanthroline, p-MOPIP = 2-(4-methoxypheny1)-imidazo[4,5f] Markman (2003), Janaratne et al. (2007) phenanthroline) (dl-OMe) and its enantiomer Delta/Lambda-[Ru(phen)(2)p-MOPIP](2+) (Delta/Lambda-OMe) could bind to and stabilize G-quadruplex DNA structure in telomeres, and inhibit telomerase activity. In this study, cytotoxic activity of these Ru complexes was studied by MIT assay. The anti-tumor mechanisms of Lambda-OMe were investigated using TRAP assay, Western blot analysis, flow cytometry, Hochest staining, and RT-PCR Results showed that among several Ru complexes, Lambda-OMe demonstrated a better anti-tumor activity against gastric cancer cell line (MGC-803), and had less effect on normal gastric epithelial cell. Lambda-OMe effectively inhibited the cell growth by inhibiting cellular telomerase activity, triggering cell cycle arrest, and inducing apoptosis of MGC-803 cells. The inhibitory effect on telomerase activity was associated with the altered expression of telomere-related proteins TRF1 and TRF2. Cell-cycle arrest was associated with increased levels of P21 mRNA. Apoptosis of MGC-803 cell was triggered by modulating the expression of apoptosis-related genes Bax, Bcl-2, and caspase-3. Overall, the results suggest that Lambda-OMe may be a new promising agent for human gastric cancer therapy. (C) 2016 Elsevier B.V. All rights reserved.