It has been proposed that cells with low levels of TopoIIa respond better to the types of drugs that inter fere with the catalytic activity http://www.selleckchem.com/products/Tipifarnib(R115777).html of the enzyme, while cells with high TopoIIa levels are most resistant. This could explain why, compared to uninduced Gem9 cells, induced Gem9 cells were resistant to these drugs, since geminin overexpression reduced the level of TopoIIa on the chromatin. The other types of TopoIIa drugs have the potential to induce DNA DSBs by stabilizing TopoIIa on DNA and prevent its religation activity during chromosome decatenation. It has also been proposed that these drugs induce a DSB for every drug stabilized TopoIIa enzyme. Thus sensitivity Inhibitors,Modulators,Libraries to this type of drugs increases with the level of the chromosome bound TopoIIa.
Low chromosome bound TopoIIa was detected in cells expressing endogenously or exogenously, so over expression of geminin could explain resistance to this type of drug as well. This important aspect of our study implies that the efficacy of all Inhibitors,Modulators,Libraries types of TopoIIa directed drugs should increase if combined with geminin inhibitors. Our previously published results and those pre sented in this study are in principle agreement with those published recently by Zhu et al. Those authors claimed that selective killing of cancer cells could be achieved by inhibiting geminin activity. Whereas they claimed that normal cells depleted of geminin continue to proliferate normally, we showed earlier that geminin silencing inhibited progres sion of immortalized HME cells from the M to G1 phase with minimal effect on S phase progression.
Furthermore, they proposed that cancer cells depleted of geminin specifically rereplicate their genomes and that their nuclei became giant and Inhibitors,Modulators,Libraries underwent apoptosis. However, we proposed that geminin has a fundamental cytokinetic function, whereas its S phase is redundant. This discrepancy could be due to differences in the cell types and or the techniques used. Another possible rea son for this incongruity is that the system cells used in the Zhu et al. study continued to express cyclin A, while in the HME cells we observed no cyclin A expres sion in geminin silenced cells. It would be interest ing in future studies to determine whether, in breast cancer cell lines, for example, geminin silencing also induces rereplication as reported by Inhibitors,Modulators,Libraries Zhu et al. However, we doubt this will be the finding, because in a future publication we will show that continuous geminin silencing inhibits the proliferation of MDAMB231 cells in vitro as well as tumor Inhibitors,Modulators,Libraries formation in a mouse xenograft model. Also in contrast selleck screening library to the data presented by Zhu et al. in our work it is geminin overexpression, not its silencing in HME cells, that triggers the formation of cells contain ing 4 N DNA content in vitro.
No related posts.