Additionally, Cdc42 inhibition by AZA197 resulted in increased apoptosis in vivo and in vitro. More over, colon cancer cells overexpressing PAK1 have higher migration rates, whereas down regulation of PAK1 signifi Crenolanib AML cantly reduces cell migration. This is in line with our findings of reduced Inhibitors,Modulators,Libraries SW620 cancer cell migration follow ing AZA197 treatment. Furthermore, the ERK dependent pathway is required in PAK1 mediated colon Inhibitors,Modulators,Libraries cancer cell migration and invasion. Consequently, the observed down regulation of the Cdc42 PAK1 signaling pathway could therefore constitute the major effector pathway of AZA197 in colon cancer. However, there are some limitations to the interpret ation of the potential effects of AZA197 on cell prolifer ation and cancer cell migration and invasion in this study.

Our data in SW620 cells suggest that AZA197 may impact cancer cell viability at concentrations that inhibit Cdc42, cell proliferation and actin cytoskeletal changes in SW620 cells. Impaired Inhibitors,Modulators,Libraries cell viability may be expected because in addition to regulation of cell migra tion and invasion, Cdc42 and the downstream signaling mediator PAK1 have also been implicated in regulation of the cell cycle, thereby affecting cell survival and apoptosis, which is in line with our findings in SW620 cells. In contrast, in HT 29 cancer cells, viability and proliferation were not affected by AZA197 at concentrations that significantly inhibit Cdc42 activity as well as cancer cell migration and invasion. Moreover, at concentrations that inhibit Cdc42 mediated mor phological changes, Inhibitors,Modulators,Libraries we do not see significant effects of AZA197 on cell viability in HT 29 cells.

Inhibitors,Modulators,Libraries These findings rather suggest cell line dependent variations in AZA197 effects than a general unspecific effect of AZA197 on cell viability. Importantly, our data also demonstrate that AZA197 does not selleck Afatinib affect the viability of fibroblasts at effective concentrations indicating AZA197 to be a viable, anti cancer therapeutic agent with only minor toxicity to normal cells. Our studies in athymic nude mice revealed no changes in body weight or gross indi cations of toxicity. It may therefore be expected that use of AZA197 as an anti cancer thera peutic in colon cancer would result in a varying response to the compound depending on the specific genetics of the cancer cells. Conclusions In summary, the present study describes a novel small molecule inhibitor which can be used to effectively inhibit the Rho GTPase Cdc42 in the treatment of KRAS mutant colorectal cancers. We provide evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro survival signaling pathways via PAK1 ERK signaling and reduces colon cancer cell migra tion and invasion.