Our benefits showed that treatment method with apicidin alone likewise as cotreatment with apicidin and TRAIL induced down regulation of Bcr Abl, and Bcr Abl inhibitor STI sensitized K cells to TRAIL induced apoptosis as did apicidin, suggesting that apicidin could overcome TRAIL resistance in K cells through down regulation of Bcr Abl. As mentioned previously, Bcr Abl exhibits a constitutive tyrosine kinase action top for the activation of numerous signaling molecules such as PIK AKT kinase and protects cells from apoptosis . Our benefits showed that cotreatment with apicidin and TRAIL decreased the degree of PIK and p AKT. Down modulation of PIK and AKT action by treatment with the LY re sensitized K cells to TRAIL as did apicidin. Consistent with these results, Steelman et al. reported that PIK AKT pathway plays an important purpose in CML leukemogenesis by transducing the Bcr Abl signal. For this reason, PIK AKT pathway seems to become involved in TRAIL resistance, plus the inhibition of this pathway by apicidin contributes to the sensitization to TRAIL induced apoptosis in Bcr Abl dependent pathway. Cuni et al. reported that a sustained activation of PIK NF ?B pathway is critical for the survival of continual lymphocytic leukemia B cells.
NF ?B, which continues to be reported to be constitutively up regulated in lots of cancer cells, may well play a significant part in attenuating the effects of TRAIL by the upregulation of anti apoptotic Bcl xL, that is just lately identified as a primary modulator of TRAIL sensitivity and represented Wnt inhibitors an necessary NF ?B dependent survival factor towards TRAIL mediated apoptosis . Without a doubt, inhibition of NF ?B signaling by numerous agents has become shown to boost TRAIL cytotoxicity in countless cellular designs . In our study, cotreatment with apicidin and TRAIL reduced nuclear translocation and DNA binding activity of NF ?B, which may possibly result in TRAIL cytotoxicity by down regulation of Bcl xL. Furthermore, Lamothe et al. reported that ectopic expression of Bcl and Bcl xL inhibits the apoptosis induced by TRAIL by way of suppression of caspase and , and Bid cleavage in human acute myelogenous leukemia cell line HL .
Seeing that activation of caspase and Bid Cisplatin cleavage was observed immediately after cotreatment with apicidin and TRAIL, it can be advised that apicidin mediated sensitization of TRAIL induced apoptosis may well end result from down regulation of Bcl xL expression that’s dependent on NF ?B exercise. On the other hand, considering Secchiero et al. recommended that TRAIL stimulated caspase and nitric oxide synthase exercise, and both pathways cooperate in mediating development inhibition of K, there exists a probability that activation of NOS may perhaps be also involved in apicidin mediated TRAIL induced apoptosis in K cells. Even so, more research might be needed to be proven.