Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells.
Pancreatic cancer is a common and lethal malignancy. Pancreatic cancer cells overexpress multiple anti-apoptotic factors and death receptor decoys, and are strongly resistant to radiation and to 5-fluorouracil (5-FU)- or gemcitabine (Gem)-based chemotherapy regimens. We have found that low-dose proteasome inhibitor PS-341 and histone deacetylase inhibitor trichostatin A (TSA) synergistically induce cytotoxicity in a panel of eight diverse pancreatic cancer cell lines. Combining TSA with PS-341 effectively inactivated NFkappaB signaling, downregulated the predominant endogenous anti-apoptotic factor Bcl-XL overexpression, and disrupted MAP kinase pathway. The combined drug regimen effectively inflicted an average of 71.5% apoptotic cell death (55.2-80%) in diverse pancreatic cancer cell lines by activating the intrinsic apoptotic pathway.


CONCLUSIONS
The TSA/PS-341 regimen may represent a potential novel therapeutic strategy for pancreatic cancer.
Bai
Jirong
J
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221, USA. jbai@bidmc.harvard.edu
Demirjian
Aram
A
Sui
Jianhua
J
Marasco
Wayne
W
Callery
Mark P
MP
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011480:Protease Inhibitors / Q000633:toxicity; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000633:toxicity*; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051020:bcl-X Protein; C012589:trichostatin A; D000069286:Bortezomib; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases