The re sults showed that, different from PKI, H 89 inhibited the proliferation and migration of A549 cells. These results were consistent with the pro tein and gene levels of VEGF, IL 8 and IL 6 of A549 cells under PKI and H 89. Discussion In this study we showed that NE spurred tumor growth in the murine melanoma model treated with sunitinib by gavage in vivo and could be inhibited by propranolol. We also identified that NE upregulated VEGF, IL 8, and IL 6 protein levels in B16F1 cells in the presence or ab sence of the treatment with sunitinib at the concentra tion equal to IC50, which was blocked by propranolol. In addition, NE dependent up regulation in both protein and gene levels of VEGF, IL 8, and IL 6 was observed in human lung adenocarcinoma cells in which B AR cAMP PKA signaling pathway was proved as the im portant mechanism.
Chronic stress has been acknowl edged SH-4-54 cost as an important factor affecting patients with cancer and the effect of chronic stress may be persistent during the process from diagnosis for cancer to death of cancer. The activation on sympathetic nervous system by stress gives rise to the increased level of catechol amines resulting in several biological effects via ARs such as VEGF caused stimulation in angiogenesis, raised levels of cytokines including IL 8 and IL 6. These effects were also proved in our study and found as at least a part of factors attenuating the efficacy of sunitinib in preclinical models. In order to mimic chronic stress in patients, a wide variety of stress models in animals were established, e. g.
addition of corticosterone to drinking water, transfer to a cold room at 4 C, subcutaneously selleckchem administration with NE or B2 AR agonists, restraint procedure using open ended Plexiglas cylindrical restrainers, social defeat, social isolation, unpredictable chronic mild stress, re peated social defeat, subcutaneous microosmotic pumps containing NE. However, some of stress mo dels aforementioned have limitations more or less and thus induce unpredictable impacts on tests in vivo. For addition of corticosterone to drinking water, this test might not control the volume of water drunk by animals and thus the reliable uptake of corticosterone can not be evaluated especially when uptake of water was in terrupted by the disorders in animals such as a heavy tumor burden.
For the restraint test, it was found in our laboratory that mice would adapt the open ended Plexiglas cylindrical restrainers in the later stage. So the restraint test might not sustain enough stress if the ob servation in a test in vivo should be kept for a long time. Seeing that microosmotic pumps are of the ability of pumping drugs contained incessantly for up to 4 weeks and exhibit reliable effects in mouse models, the pumps were taken into account in our re search to deal with the short half life period of NE.