Strikingly, chemotherapeutic drugs influenced the expression patt

Strikingly, chemotherapeutic drugs influenced the expression pattern in HCC cells. Upregulation of TRAIL-R1 and profound upregulation of TRAIL-R2 after Doxo and 5-FU treatment in both cell lines might represent a potential mechanism of chemotherapy-mediated TRAIL sensitization. Interestingly, TRAIL-R3 (DcR1) was also upregulated after chemotherapy. This could also represent a mechanism of TRAIL selleck catalog resistance upon chemotherapy, since TRAIL-R3 acts as a decoy receptor. Notably, upregulation of TRAIL receptors in Huh7 cells which express mutated p53 suggests that receptor regulation occurs independently from p53[30]. Several mAbs targeting TRAIL receptors and recombinant TRAIL agonists have already entered clinical trials[31-33].

In order to analyze the efficacy of different TRAIL compounds, we included LBY135, a chimeric antibody targeting TRAIL-R2, recombinant TRAIL and SkTRAIL in our study. We demonstrate that crosslinking elements IgG F(ab)��2 are mandatory for LBY135-induced apoptosis. Consistent findings were obtained for recombinant TRAIL, where combination with an enhancer is necessary to induce apoptosis. Comparing the death-inducing capacities of LBY135, TRAIL and SkTRAIL in HCC cells, we assume that TRAIL-R2 plays a major role, which would be in line with observations in colon and breast cancer[34]. In contrast, it has been shown that chronic leukemia cells are selectively sensitive to TRAIL-R1[35]. Taken together, it appears likely that a cell type dependency determines the efficiency of TRAIL-mediated apoptosis induction, even if both TRAIL-R1 and -R2 are expressed.

Chemotherapeutic drugs such as Doxo and 5-FU have shown limited efficacy for the treatment of HCC[26]. However, anti-tumoral effects have been described for Doxo if administered into the liver via chemoembolization[26,36]. In our study we aimed to discover whether the combination of TRAIL with chemotherapy exerts anti-tumoral effects in HCC. Importantly, chemotherapy with Doxo or 5-FU increased TRAIL susceptibility in Hep-G2 cells and sensitized Huh7 cells towards TRAIL, opening the possibility of a treatment regime including reduced doses of chemotherapeutic drugs in combination with TRAIL. The multi-kinase inhibitor Sorafenib has recently been approved for the therapy of advanced HCC. Sorafenib acts by inhibition of the RAF/MEK/ERK pathway and downregulation of MCL-1, leading to a disruption of survival signals in HCC cells[4,37].

In combination with TRAIL, Sorafenib profoundly increased apoptosis induction advocating TRAIL as a potential and effective agent for HCC treatment along with Sorafenib. There is evidence that constitutive activation of various antiapoptotic pathways is a basic principle Carfilzomib of tumor growth, cell cycle progression and apoptosis resistance. A well described antiapoptotic pathway is the PI3K/Akt signaling pathway, found activated in several tumor entities, including HCC[38].

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