The family of HDACi represents a novel approach in oncological research. In defined predominantly haem atological tumour entities, HDACi have already passed the selleckchem CHIR99021 stage of experimental research and been investigated clinically. Regarding PDAC, promising results have been shown using SAHA, TSA, butyrate and some other histone deacetylase inhibitors in experimental studies. Belinostat is a novel member of the family with a distinct pan HDAC inhibitory effect. It has been shown to be strongly effective in experimental settings of ovarian, bladder and colon cancer, as well as haemato logical tumour entities. Consecutive clinical trials have proven an anti tumour effect of belinostat as a monotherapy in T cell lymphomas and thymomas.
In addition, belinostat has demonstrated beneficial effects in combination with other anti cancer drugs for the treatment of ovarian and bladder cancer, CUP, multiple myeloma and acute myeloid leukaemia. Despite these findings, no data are available concerning belinostat in the context of PDAC treatment. Consequently, in the present study, the efficacy of belinostat for PDAC treat ment was investigated in experimental in vitro and in vivo settings for the first time. Comparable to the results of previous studies in blad der, colorectal or hepatocellular carcinoma, we found a strong dose dependent antiproliferative ac tivity of belinostat in three pancreatic cancer cell lines with an IC50 concentra tion in the nanomolar range, similar to other tumour entities. This antiproliferative effect can be explained by a strong proapoptotic activity in pancreatic cancer cells, demonstrated by annexinV/propidium iodide staining.
This is in line with other studies on AML and hepatocellular carcinoma cells, underlining that apoptosis induction is an important mechanism of the anti tumourous effect of HDACi, and particularly beli nostat. As apoptosis induction is an important mechan ism of anti cancer chemotherapy, we tested the influence of concomitant use of belinostat and gemcita bine. As described in studies with other HDACi like tri chostatin A and 4 phenylbutyrate , the combination of gemcitabine and belinostat strongly enhanced the proapoptotic effects of each substance alone. This may be due to the expression of proapoptotic proteins like Caspase 8 and Bid, and activation of the gemcitabine mediated JNK pathway.
Increase in histone H4 acetylation has been shown to be helpful in monitoring belinostat activity. Conse quently, we examined belinostat dependent expression of acH4 in PDAC cells. Acetylation of H4 was increased in all cell lines tested, confirming the inhibitory effect of belinostat on HDAC activity in pancreatic cancer cells. Cyclin dependent kinase inhibitor Brefeldin_A p21Cip1/Waf1 is a key protein participating in cell cycle regulation.