The
proteasome inhibitor bortezomib (B) has been shown to enhance
gemcitabine (G) effects against pancreatic ductal
adenocarcinoma (PDAC).
Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic
cytokine. We tested the combination effects of
bortezomib,
gemcitabine and EMAP in experimental PDAC.
Bortezomib inhibited the in vitro proliferation of PDAC and endothelial cells, with additive effects in combination with
gemcitabine or EMAP.
Bortezomib induced apoptosis as observed by PARP-1 cleavage; it also increased the expression of p21 (>27-fold) and p27 (>2.5-fold), with additive effects in combination with
gemcitabine and EMAP.
Bortezomib caused a decrease in the expression of the antiapoptotic
protein Bcl-2, and an increase in the proapoptotic
protein Bax and in p53.
Bortezomib had no effect on the intracellular levels of full length or mature EMAP. An in vivo murine xenograft model showed extended survival in all combination groups except B + E compared with control or monotherapy, but no benefit of B + E + G over E + G. The relative local
tumor growth compared to controls after
bortezomib, EMAP,
gemcitabine, B + G, E + G or B + E + G was 92, 52, 48, 36, 18 and 35%, respectively. Our results show that in vitro
bortezomib had an antiproliferative and proapoptotic effect, and it's combination with
gemcitabine and EMAP increased these effects. In vivo,
bortezomib had no antitumor effect by itself, enhanced
gemcitabine effects in combination, but failed to further significantly improve the E + G combination benefit. The potential value of
proteasome inhibition in
experimental therapy approaches for PDAC appears to relate primarily to the combination with the cytotoxic
drug rather than with the antiendothelial agent.