At these concentrations, the inhi bition in cell proliferation of other PDAC lines in JP, Gem and JP Gem groups were 54%, 10% and 79% for Panc 1. 42%, 56% and 77% for BxPC 3. and 9%, 43% and 77% for MIA PaCa 2, respectively. Effect of JP and Gem on PDAC apoptosis We examined if the inhibition concerning in AsPC 1 cell viability by JP and Gem could in part be due to induction of apop tosis. Annexin VPI staining assay revealed an increase in early Inhibitors,Modulators,Libraries apoptotic cells by JP and Gem treatment that was further increased by combination of these agents. At 10 uM concentration of either agent, the percentage of early apoptotic cells was 17% in con trols, 26% in JP or Gem, and 38% in the JP Gem group. We also measured cleavage of PARP 1 protein, a cas pase dependent apoptosis marker protein, after JP and Gem treatment.

Inhibitors,Modulators,Libraries A significant increase in the expression of cleaved PARP 1 protein was observed after treatment Inhibitors,Modulators,Libraries with JP, but not after exposure to Gem. Combination effects of JP and doxorubicin or docetaxel on PDAC cell proliferation We next evaluated if JP can sensitize other chemothera peutic agents. In vitro WST 1 assay revealed that JP, Dox and DT inhibited the proliferation Inhibitors,Modulators,Libraries of all four PDAC cell lines tested in a dose dependent manner. Interestingly, the combinations of JP with either doxorubicin or docetaxel had additive effects on inhibition of proliferation of PDAC cell lines. At intermediate concentrations of these agents, inhibi tion in cell proliferation in AsPC 1 cells in JP, Dox, DT, JP Dox and JP DT groups were 40%, 39%, 48%, 73% and 73%, respectively.

Similar additive combination effects Inhibitors,Modulators,Libraries of JP with Dox or DT were observed regarding selleck Alisertib Panc 1, MIA PaCa 2 and BxPC 3 proliferation. Evaluation of PARP 1 cleavage after JP, Dox and DT treatment by Western blot analysis revealed that Dox and DT had no effect on PARP 1 cleavage, while JP exposure led to a significant increase in PARP 1 clea vage. In vivo effects of JP addition to gemcitabine and docetaxel The antitumor impact of JP, Gem and DT, either alone or in combination, was evaluated in murine PDAC xenografts. In an orthotopic Panc 1 xenograft model, tumor weights were measured at completion of therapy and compared to tumors harvested at 24 hours of ther apy. The increase in tumor weight was 87% in controls, while Gem and JP treatment alone trended towards decreased tumor growth, albeit not significant. JP Gem combination treatment resulted in decreased tumor weight compared to that at treatment start, with a mean reduction of approximately 30%. In survival studies with maintenance therapy, a statistically significant improvement in animal survival was observed in mice treated with the combina tion of JP Gem compared to controls or single agent treatment with JP or Gem.