In our in vitro experiments, we observed that sorafenib at ten uM lowered the phosphor ylation of MAPK suggesting that it acts as a Raf kinase inhibitor. Furthermore, we also found that sorafenib potentiated the anti proliferative and pro apoptotic effi cacy of NVP BEZ235 which targets PI3K Akt mTOR signaling pathway. Consistent with this observation, pre vious research have shown that the antitumor activity of mTOR inhibitors is increased when the Raf MAPK sig naling pathway is concomitantly inhibited. In vivo, sorafenib did not minimize cancer cell proliferation and didn’t induce cancer cell apoptosis. We rather observed that sorafenib reduced tumor angiogenesis suggesting that the mechanism of action of sorafenib is distinct in vitro and in vivo.
The rationale to use NVP BEZ235 with agents target ing angiogenesis can also be according to the observation that NVP BEZ235 has tiny impact on tumor angiogenesis in xenograft models of RCC. Targeting the PI3K read what he said Akt sig naling pathway offers opposite effects on angiogenesis according to the model utilized. On one hand, blocking endothelial Akt with rapamycin results in decreased angiogenesis and NVP BEZ235 decreases VEGF induced angiogenesis. On the other hand, tumors implanted into transgenic mice lacking Akt grow faster and present an improved vasculature. As a result the angiogenic impact in the inhibition with the PI3K Akt sig naling pathway in endothelial cells may possibly be unpredict in a position. Within this study, we found that NVP BEZ235 only slightly decreased tumor angiogenesis in 786 0 xenografts. A related impact was observed in Caki 1 xenografts which was, on the other hand, not significant.
Consistently, no reduction of tumor angiogenesis was identified in RCC xenografts treated with NVP BEZ235. In addition, an increase of tumor angiogenesis has been described in 786 0 xenografts treated with LY294002, a PI3K inhibi tor. Thus, agents that Trametinib manufacturer target the PI3K Akt pathway have tiny effect on tumor angiogenesis in renal cancer xenograft models. This suggests that their antitu mor efficacy could be elevated in mixture with anti angiogenic drugs. Diverse possibilities of mixture therapy exist, includ ing the inhibition of different targets in the exact same path way, or the inhibition of two separate pathways. As NVP BEZ235 inhibits various effectors in the PI3K Akt mTOR sig naling pathway, a simultaneous vertical and horizontal blockade is achieved by combining NVP BEZ235 and sorafenib. The possible dilemma of such mixture therapy may be the enhanced toxicity. Even though we did not come across any evident toxicity, further studies are expected to totally characterize the toxicity profile of this therapy.