Notably, in agreement

Notably, in agreement with previous studies and with the role of NFB signaling pathway in melanoma growth and survival, we found that NBD peptide, as a single agent, was able to impair mel anoma cell proliferation in a concentration dependent manner. However, it must be pointed out that the NBD peptide concentration exploited in combination with TMZ only moderately affected M10 cell proliferation when used alone. Moreover, TMZ IC50 values deter mined in presence of the NBD peptide were signifi cantly lower than those determined in the absence of the NFB inhibitor, not only when they were evaluated using BG treated cells as control group, but also when they were calculated using BGNBD treated cells as control group. These findings show that TMZ is more efficient in M10 cells when associated with the NFB inhibitor.

Notably, the same drug combination was also found to be more active than TMZ alone in HCT116 3 6 cells, although NBD peptide TMZ showed only additive effects on cell growth. So far, a small number of studies have addressed the effects of TMZ on NFB pathway with some discordant Inhibitors,Modulators,Libraries results. Amiri et al. demonstrated that exposure to TMZ increased RelA nuclear localization in melanoma cells Inhibitors,Modulators,Libraries and that bortezomib, an inhibitor of proteasome able to impair NFB activation, potentiated TMZ induced suppression of melanoma cell growth both in vitro and in a murine xenograft model. Using an NFB responsive luciferase reporter, Ohanna et al. also observed NFB activation in melanoma cells exposed to TMZ. On the other hand, Yamini et al. and Schmitt et al.

demonstrated that TMZ treatment impaired NFB transcriptional activity in glioblastoma cells. In these cells, TMZ induced activation of Chk1 led to pho phorylation of the NFB1p50 subunit on Ser329, dis rupting the DNA binding ability of NFB dimers containing this subunit. The results of our study are consistent Inhibitors,Modulators,Libraries with the Inhibitors,Modulators,Libraries findings of Amiri et al. and Ohanna et al. However, we also show for the first time that, depend ing on the cell line, both the canonical and non canonical pathway of NFB activation can be elicited by TMZ and that AKT plays a crucial role in the drug induced activation of both pathways. On the other hand, the discrepancy between our results and those of Yamini et al. and Schmitt et al. might depend on the different cellular models utilized to assess the effect of TMZ on NFB activity.

Inter Inhibitors,Modulators,Libraries estingly, Hirose et al. have shown that in glio blastoma cells selleck catalog TMZ treatment causes a decrease in the endogenous levels of AKT phosphorylated on Ser473. Previous investigations have also shown that activated AKT is able to phosphorylate Chk1 on Ser280, leading to inactivation and cytoplasmic localization of this check point kinase. It is possible to speculate that TMZ treatment could result in NFB activation or inhibition, depending on whether in the cell line under investigation the drug activates or not AKT in addition to Chk1. How ever, further studies are required to address this issue.

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