Inhibition of PARP generates single-strand breaks that are subsequently encountered by the replication fork, which gives rise to DSB substrates for homologous recombinational repair. Sensitivity to PARP inhibitors is not limited to BRCA1 or BRCA2 defects but to defective homologous recombinational repair in general.
Histone deacetylase inhibitors leads to increased levels of p21 and p27, as well as induces the levels of prodeath proteins (eg, Bax, Bak, and Bim) and down-regulates antiapoptotic proteins, (eg, Bcl-xL, XIAP, survivin, and AKT) in human leukemia cells.
To estimate the synergy between HDAC inhibitor andPARP inhibitors, many studies has been done in the last years.
A systematic screening effort of anti-cancer agents in combination with PCI-24781 in the colon tumor cell line HCT116 revealed that one of the strongest synergies occurred with PARP-selective inhibitors, including PJ34. HCT116 cells treated with both PCI-24781 and PJ34 in combination resulted in a significantly more than additive effect on apoptosis as assayed by Annexin V staining compared with either agent alone[1].
The HDAC inhibitors also have relations with PARP protein.
Cotreatment with AMN107 and LBH589, simultaneous induction of Bim and attenuation of Bcl-xL is associated with more PARP cleavage, which is due to increased activity of the effector caspases 3 and 7 during apoptosis and also causes greater attenuation of p-AKT, p-STAT5, p-CrkL, Bcl-xL, and c-Myc but induces more p27, Bim, and PARP cleavage in K562 cells[2].
LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, could induce PARP cleavage, which is an indication of caspase activation and apoptosis. Whereas incubation of cells with Z-VAD-FMK inhibited LAQ824-induced PARP cleavage, this did not prevent LAQ824-induced androgen receptor degradation.
NVP-LAQ824 induces time- and dose-dependent histone hyperacetylation, p21 up-regulation, and PARP cleavage. transient up-regulation of p21 coinciding with G1 arrest after treatment with NVP-LAQ824. Cell death signaling pathways subsequent to p21 up-regulation involve cleavage of pro-caspase-8, pro-caspase-9, pro-caspase-3, and PARP cleavage of an 85-kDa product. However, up-regulation of procaspases and uncleaved PARP was not seen, suggesting that these events are not directly a result of increased procaspase transcriptional activity.
Lenalidomide induced cleavage of PARP into an atypical approximate 60-kDa fragment, reminiscent of apoptosis mediated by the protease calpain, whereas TRAIL/Apo2L resulted in "classic" cleavage of PARP to an approximate 85-kDa fragment. This SAHA-induced pattern of PARP cleavage is reminiscent of that observed in human breast carcinoma cells treated with the cytotoxic agent β-lapachone, which is mediated by the protease calpain[2].
References
[1] Shanthi Adimoolam,et al. PNAS December 4, 2007 vol. 104 no. 49 19482-19487
[2] Warren Fiskus,et al. Blood July 15, 2006 vol. 108 no. 2 645-652
[3] Liwei Chen,et al. Mol Cancer Ther September 2005 4; 1311
Related Posts
Some good news between HDAC and PARP
[1] Shanthi Adimoolam,et al. PNAS December 4, 2007 vol. 104 no. 49 19482-19487
[2] Warren Fiskus,et al. Blood July 15, 2006 vol. 108 no. 2 645-652
[3] Liwei Chen,et al. Mol Cancer Ther September 2005 4; 1311
Related Posts
Some good news between HDAC and PARP
About the Author
Neuro
Buy inhibitors for research work. Well known by scientists and researchers worldwide for enzastaurin Compound Libraries, Erlotinib,... (show bio)
No comments:
Post a Comment