In contrast to what was observed human esophagil cancer cell lines, Liu et al. reported that PS-341 upregulates DR5 also as c-FLIP and survivin in human non-small cell lung carcinomas cells . As mentioned earlier, c-FLIP is degraded by means of a ubiquitin-proteosome program. Hence, PS-341 really should enhance c-FLIP and reduce apoptosis. Interestingly, Zhao et al. have shown that PS-341 decreases c-FLIP at the gene level . The Bcr-Abl kinase inhibitor imatinib mesylate is presently the traditional treatment for continual myeloid leukemia . Hama? et al. reported that Imatinib mesylate increases human melanoma cell sensitivity to TRAIL-induced cell death by immediately downregulating protein amounts of c-FLIP variants. Interestingly, Park et al. showed that silencing the Bcr-Abl in K562 leukemia cells led on the downregulation of c-FLIPL and subsequent increase to TRAIL sensitivity. As shown in Table 2, a number of agents identified to have an impact on many targets and signaling pathways in cancer cells also result in degradation of c-FLIP variants .
Moreover, several compounds have already been shown to inhibit expression of c-FLIP variants, but whether these agents result in degradation of those proteins or silence their transcription continue to be to be noticed. Nutlin-3, a compact molecule antagonist of MDM2 which inhibit the p53-MDM2 interaction and activates p53 signaling was lately proven to lower expression of c- FLIPS and c-FLIPL and was synergistic with TRAIL in Vandetanib triggering cell death . Moreover, Ozarelix, a gonadotropin-releasing hormone antagonist , celecoxib, a cyclooxygenase-2 inhibitor , the chemopreventive agent, all-trans-retinyl acetate , smac mimetic compounds , and sunitinib, an orally administered tyrosine kinase inhibitor decreased expression of c-FLIP. On top of that, downregulation of c-FLIP by a specific microRNAs greater taxol-induced apoptosis , supporting our former report that silencing c-FLIP variants increases Taxoltriggered apoptosis .
Gemcitabine was also not too long ago proven to inhibit expression of c- FLIP variant in pancreatic cancer cells , but whether or not it inhibits the transcription, enhances degradation, or prevents translation of c-FLIP remains to become identified. Latest data plainly show that ataxia telangiectasia mutated kinase action modulates c-FLIPL and c-FLIPS compound libraries selleck chemicals protein amounts in response to DNA damage . Furthermore, the radiomimetic drug Neocarzinostatin may perhaps trigger the downregulation of c-FLIP isoforms by inducing the activation with the ATM kinase in response to DNA damage . ATM kinase activity negatively modulates the stability of c-FLIPL and c-FLIPS on the protein degree, thereby marketing the sensitivity to apoptosis induction by Fas , a TRAIL-R1/R2-related death receptor .