Jaime Modiano, The canine D17 OSA cell line and human OSA c

However, at 24 h post irradiation there is a distinct difference in caspase activation between KU-0063794 ic50 irra diated cells and cells treated with the com bination of irradiation and WEE1 inhibitor, Taken together, this implies that cells treated with the WEE1 inhibitor are forced to proceed through the G2 cell cycle checkpoint into mitotic entry despite the presence of DNA damage and are therefore sensitized to g irradia tion induced apoptosis. Discussion In this work, we explore the possibility to use WEE1 inhibition as a new therapeutic strategy in OS.<br><br> The use of WEE1 inhibitor PD0166285 to obtain radiosensitiza tion in various malignancies has been reported pre viously, The radiosensitization effect is described to be particularly effective in, if not limited to, p53 deficient malignancies, Interestingly, we Lenalidomide ic50 have found that our tested cell lines can all be sensitized to irradiation, regardless of their p53 status, This, we ascribe to the idea that a defective G1 checkpoint is not necessarily caused by p53 mutations alone but rather a disruption in the p53 pathway, which can be caused by other aberrations within this pathway. We show that after irradiation, OS cells accumulate in a predominant G2 arrest, the abrogation of which effectively leads to mitotic catastrophe. As was reported previously, our results con firm that normal cells remain unaffected by WEE1 inhi bition after irradiation. We tested human primary osteoblasts for their response to irradiation in the pre sence or absence of WEE1 inhibitor. While there was a minor effect of irradiation on cell viability, no radiosen sitization by PD0166285 was observed.<br><br> This is likely explained by a functional G1 checkpoint with concurrent wild type p53 expression. This indicates that WEE1 inhibition is a safe strategy to apply in OS patients because the radiosensitization would be cancer cell specific. Apart from being a regulator of mitotic LY294002 構造 entry, WEE1 has been described to also affect other important cellu lar processes, such as regulation of mitotic spindle for mation, positioning and integrity, microtubule stabilization and heat shock protein 90 phos phorylation, In this paper, we have not exam ined these phenomena, but it could be that the disruption of one of these processes contributes to the observed phenotype. It may be interesting to study these additional effects in the future.<br><br> Timing of combination therapy is important to obtain optimal treatment efficacy. It was reported that CDC2 is transiently phosphorylated to induce an arrest at the G2 M checkpoint for 12 h after irradiation treatment and that DNA damage could be repaired in 12 24 h after irradiation, Our results support this; in irra diated cells, we observed only few remaining foci of DNA damage after 24h, whereas cells treated with irra diation and WEE1 inhibitor had many residual foci after 24h, indicating that they were unable to perform DNA repair. This suggests that DNA damaged cells are espe cially susceptible to WEE1 inhibitor in the first 12h after induction of DNA damage. In our experimental set up, the cells were treated with WEE1 inhibitor directly after irradiation and show a good sensitization.

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