Inhibition of the IKK NFB activation pathway selleck chem is considered an effective target for many anticancer drugs. NF kB inhibition in cancer cells has been shown to enhance chemotherapeutic response. BT has also been reported to inhibit NF kB signalling via inhibition of IkB phosphorylation in vitro. Given the rele vance of the NFB pathway in cancer, we assessed the effect of BT on phospho NFB p65 and subsequent ef fect on NF Inhibitors,Modulators,Libraries kB regulated proteins such as pIkB, pbcl 2, bcl xL, xIAP. Immunoblot analyses of whole cell lysate reveal decreased phospho NFB p65 expression with increasing treatment time. BT treatment also down regulated the expression of pIkB. Suppression of prolif eration, induction of apoptosis and G1 S cell cycle arrest can all be due to inhibition of phosphorylation of NF kB and IkB.
Inhibitors,Modulators,Libraries BT can affect the DNA binding activity of NF kB directly via oxidation by ROS and or indirectly by inhibiting phosphorylation of NFB and IkB. Phosphorylation of p65 at ser536 is essential for the DNA binding activity of NFB and it is known to be mediated via the PI3 kinase pathway. Because BT also decreased pAkt expression, BT appears to indirectly reduce the DNA binding activity of NFB and affect the expression of NFB regulated anti apoptotic proteins such as pIkB, pbcl 2, bcl Inhibitors,Modulators,Libraries xL, xIAP. Indeed, we observed that NF kB regulated proteins XIAP, bcl xl, pbcl2 were down regulated upon BT treatment. XIAP is known to prevent apoptosis through up regulation of PI3k Akt cell survival signalling pathway. Inhibitors,Modulators,Libraries Down regulation of XIAP induces apoptosis and increases cisplatin sensitiv ity.
Inhibition of Bcl xl may increase sensitivity to drugs such as carboplatin. Expression of Bcl 2 is important in protection from drug induced apoptosis in ovarian cancer thereby contributing to chemo resistance. These reports implicate NF kB Inhibitors,Modulators,Libraries as a desirable tar get for anticancer agents in ovarian cancer. Our results demonstrate inhibitory effect of BT on NF kB regulated proteins in ovarian cancer cell lines. BT treatment may promote apoptotic role for NFB by repressing anti apoptotic gene expression. Our results indicate an import ant role for NF kB in BT induced cytotoxicity. However, further studies are required to confirm role of NF kB in the anti tumor effects of BT in ovarian cancer cell lines. Autotaxin inhibition was considered major mechanism of action of BT.
Previously BT was shown to inhibit solid tumor growth in several preclinical cancer models by targeting ATX. ATX plays a major role in modulation of the cellular process through its en zymatic production of lysophosphatidic acid. ATX is known to increases the aggressiveness and invasive ness of transformed cells, and directly correlates with tumor stage cause and grade in several human malignancies, including ovarian cancer. ATX was shown to delay carboplatin induced apoptosis in ovarian cancer cells. ATX inhibition was a proposed mechanism of action of BT in a melanoma model via inhibition of cell migration and invasion.