Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer.
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.
Awasthi
Niranjan
N
Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Schwarz
Margaret A
MA
Schwarz
Roderich E
RE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000008:administration & dosage; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D003841:Deoxycytidine; D000068258:Bevacizumab; D000093542:Gemcitabine