P2X Receptor that interruption of this process leads to potentiation of lethality

lymphoid malignancies, such as multiple myeloma , CLL , and non Hodgkin lymphoma cells . On the other hand, analogous interactions have been much less extensively explored in the setting of acute P2X Receptor myeloid or lymphoid leukaemias. In this context, synergistic interactions between bortezomib and vorinostat have been observed in Bcr/abl+ leukaemia cells and between the non peptide proteasome inhibitor NPI 0052 and the HDACI MS 275 or valproic acid in AML and ALL cells . In the case of combinations of belinostat and bortezomib regimen is highly effective in inducing cell death in acute myeloid and lymphoid leukaemia cells, particularly in primary blast specimens. In the case of the latter, a caveat is that, due to the relatively limited number of primary samples evaluated in the present study, the broad susceptibility of both myeloid and lymphoid acute leukaemias to this strategy cannot be generalized with certainty.
In contrast to the pronounced lethality of the belinostat/ bortezomib combination regimen in primary AML and ALL cells, toxicity toward normal CD34+ haematopoietic Clofarabine cells was significantly less. Notably, proteasome inhibitors have been shown to exert preferential toxicity toward transformed versus normal cells . Analogously, HDACIs selectively target neoplastic cells, possibly representing a consequence of up regulation of antioxidant proteins in normal cells , or alternatively, down regulation of DNA repair proteins in transformed cells . The selectivity of the bortezomib/belinostat regimen suggests that similar mechanisms might also be operative when these two classes of agents are combined.
The present findings also suggest that some of the mechanisms invoked to explain interactions between HDAC and proteasome inhibitors in B cell malignancies may also be operative in human farriers acute leukaemia cell types. There is accumulating evidence that HDACIs activate the NF jB pathway in transformed cells, and that interruption of this process leads to potentiation of lethality. HDACI induced activation of NF jB, at least in human leukaemia cells, is probably initiated from HDACI mediated DNA damage associated with oxidative stress through the atypical ATM/NEMO /SUMOylation pathway . This event leads to the phosphorylation and nuclear export of NEMO, which forms the IKK complex with other components in the cytoplasm, resulting in activation of IKKs and then the canonical NF jB pathway via IKK mediated IjBa S32/S36 phosphorylation, ubiquitination, and proteasomal degradation .
On the other hand, exposure to HDACIs also results in hyperacetylation of RelA/ p65, most likely through prevention of the deacetylation reaction via inhibition of nuclear class I HDACs . Because RelA/p65 acetylation at several lysine sites prevents its binding to de novo synthesized IjBa and nuclear export which collectively silence NF jB signalling , and/or promotes NF jB transactivation activity , prevention of RelA/p65 deacetylation by HDACIs leads to enhanced and relatively sustained NF jB activation. Furthermore, interruption of this process e.g. by pharmacological IKK inhibitors , blocks IjBa S32/S36 phosphorylation, ubiquitination, and proteasomal degradation, thereby trapping RelA/p65 in the cytoplasm and diminishing HDACI mediated RelA/p65 acetylation.

Leave a Reply

Your email address will not be published. Required fields are marked *

*

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>