Sorafenib is being tested in AML patients with limited efficacy

This service of the Raf/MAP kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of point mutations in N Raf or Ras. The PI3K pathway can be triggered in neuroendocrine tumors by deletion of the tumefaction suppressor gene PTEN. Loss of PTEN in neuroendocrine tumors increases in frequency with the loss of differentiation Lapatinib in the tumor, and loss of PTEN expression may represent an important step in the progression of neuroendocrine tumors. Cyclin D1 up regulation in neuroendocrine tumors is fairly common, as due to Ras/Raf/MAP kinase pathway activation likely. Likewise, frequent coincident activation of the Ras effectors p38/mitogen activated protein kinase and AKT/ protein kinase B together have already been reported. Hence, as in many other human tumors, activation of Ras and Ras signaling pathways probably contribute to tumor growth and progression in many neuroendocrine tumors. However, the service of these pathways also makes these tumors dependent upon Ras linked survival pathways, which need PKC for function. In the absence with this survival Organism pathway, the proliferative houses of Ras signaling are re-directed towards apoptosis. We've shown in previous work that inhibition of PKC protein or exercise in non transformed cells of numerous species by genetic knockdown, dominantnegative mutants, or modest molecule chemical inhibitors, doesn't affect their progress or clonogenic properties, suggesting that, by its selective toxicity towards aberrant Ras signaling, this approach is tumor targeted. Each one of the three neuroendocrine tumor cell lines studied here had evidence for a different profile of Ras pathway activation, with increased activity of p21Ras it self and its downstream effector pathways in the H727 cells, activation of the Raf MAPK pathway in the CNDT cells, and some relative increases in PI3K signaling in all three cell lines. Such heterogeneity Apremilast in patterns of Ras pathway activation is common in most cancers, and all these patterns of aberrant Ras signaling is enough to make tumor cells susceptible to apoptosis following PKC down-regulation. We have found in these reports that neuroendocrine tumor cell lines are vunerable to growth inhibition and apoptosis when PKC is down-regulated by specific genetic ways, or by less specific, but probably more clinically relevant, small molecule inhibitors. Some of these small molecule inhibitors demonstrate appropriate toxicity profiles in rodents. Wash-out studies suggest a length of experience of PKC inhibitors of a maximum of 24 hr is required to make a substantial influence on subsequent tumor cell proliferation. More importantly, significant reductions in tumor cell clonogenic capability in two neuroendocrine cell lines were generated by contact with a small molecule inhibitor for as little as 6 hr. Rottlerin was defined as a protein kinase inhibitor which inhibited PKC more potently than basic PKC isozymes, including and W.