To help expand examine PDGFRA as a goal for AKIs in pancreatic cancer, we analyzed the anti proliferation activity of combination therapy of PDGFR inhibitors and different AKIs. Different concentrations of imatinib coupled with a dilution of two AKIs were first considered in three pancreatic cancer cell lines. As shown in Fig. natural compound library 2, addition of 9 or 13 mM of imatinib to ZM447439 resulted in a shift of the dose?response curves in every 3 cell lines. Imatinib at 13 mM reduced the IC50 values of ZM447439 by 3 and 2 fold in the AsPC 1 and SU. 86. 86 cell lines, respectively. Improvement of imatinib to PHA 739358 also improved the sensitivity of two of the cell lines. Imatinib lowered the IC50 of PHA 739358 by 2 fold in AsPC 1 and 9 fold in SU. 86. 86. As well as the IC50 reduction in the AsPC 1 cell line, the cytotoxicity effect was enhanced by this combination at the larger concentration of PHA 739358. Table 2 summarizes the IC50 values of the AKIs in combination with imatinib after normalization with the imatinib only treatment and their proportions to the IC50 values of AKI only solutions in the three pancreatic cancer cell lines. A Meristem ratio of significantly less than 1 indicates a synergistic relationship involving the AKIs and imatinib at the concentrations tested. Because imatinib is known to inhibit other kinases besides PDGFR, to further confirm that the synergism observed is particular to PDGFR inhibition we examined another known tiny molecule inhibitor of PDGFR, sorafenib. Just like imatinib, sorafenib triggered a shift of PHA 739358 dose?response curves in AsPC 1 and SU. 86. 86 cell lines although not in BxPC 3. Because Aurora kinase inhibition has been shown to cause cell cycle arrest we examined the effects of the combination therapy of imatinib and PHA 739358 on cell cycle progression in AsPC 1 cells. As expected, PHA 739358 alone induced important G2/M charge and polyploidy. PHA 739358 considerably Ibrutinib solubility increased the G2/M population from 19. 37% to 30. 56% and the population of polyploidy cells from 5. 80% to 15. 61% within 24 h. Imatinib does not affect the cell cycle distribution of at 24 h. However, the combination therapy of both drugs triggered further induction of G2/M charge when compared with PHA 739358 alone. Similar synergistic effect was seen at both 48 and 72 h time points where in fact the combination treatment significantly increased G2/M arrest in comparison with either drug alone. Interestingly, the inclusion of imatinib to PHA 739358 reduced the polyploidy population induced by PHA 739358 at all 3 time points. For example, at the 24 h time point, the cell population with 4N DNA increased from 5.8% in 5 and untreated control. Six months in imatinib only treatment to 15. 6% in PHA 739358 only therapy, and paid down back to 5. Four to five in the imatinib plus PHA 739358 combination treatment.