Therefore, the reduction rate of GM and its analogs by P450R should adhere to the exact same order as E1/2 as is definitely the case within the presence of Tempol. Within the absence of superoxide scavengers, a numerous order of NADPH oxidation rates was obtained suggesting that the ratedetermining step is just not the reduction from the quinone mTOR target by P450R. The order of E1/2 also implies that O2 is even more readily reduced to superoxide by the semiquinone radical of GM than by the other analogs. The apparent contradiction amongst the order of hepatotoxic effect following GM > 17-AAG > 17-DMAG , and that of E1/2 is reconciled if hepatotoxicity is determined by the extent of superoxide formation instead of by the in vitro enzymatic reduction rate on the drug. Our results show that all 3 quinones are capable of participating in futile redox cycling by redox activation via the semiquinone intermediate to produce reactive oxygen species which can account for the oxidative pressure when employing these drugs. TrkA is usually a transmembrane, glycosylated receptor tyrosine kinase, which is encoded by the NTRK1 gene . Binding of TrkA to its ligand, nerve growth element induces autophosphorylation and activation of TrkA .
TrkA mediates NGF-induced signaling for differentiation in neuronal cells, e.g., neurite formation, and sympathetic neuron-like phenotype in PC-12 cells . Full NGF withdrawal or pharmacological inhibition of TrkA activity attenuates p-TrkA levels and ERK1/2 and AKT activity in PC-12 cells .
Apart from involvement in screening compounds tumors of neuronal origin, Trk mutations and translocations have been reported in breast and pancreatic cancer cells as well as in lymphoma and many myeloma cells . A TrkA mutation conferring ligand-independent pro-growth and prosurvival activity has been documented in AML . Within this mutation, a seventy five amino acid deletion of TrkA was identified, also designated as ? TrkA. This mutation is strongly leukemogenic and transforms hematopoietic stem cells by activating the PI3KmTOR pathways . A current study has demonstrated that AML cells co-express no less than one or even more isoforms in the Trk receptors . Here, a retrovirus-mediated coexpression of TrkA and its ligand NGF in 32D cells resulted in leukemia when the cells had been transplanted into mice . TrkA mRNA and protein expression has been shown to be extremely up-regulated in human AML expressing AML1-ETO . CD34+ cells expressing AML-ETO were demonstrated to respond to NGF and IL-3 stimulation by expanding in liquid culture. . In addition, recent research have demonstrated the role of neurotrophininduced TrkA signaling in non-Hodgkin lymphoma and diffuse big B-cell lymphoma cells . Heat shock protein 90 is abundantly expressed and stress-inducible, homo-dimeric, ATP-dependent molecular chaperone .