Experimental lung metastasis models MCF 7 and MCF 7 DOX cells were injected int

It has been suggested that pol II inhibitors may also prove useful in the treatment of tumours with changes in DNA repair capacity and patients with chronic DNA repair deficiency syndromes such as AT and NBS, xero derma pigmentosum and Cockayne syndrome for which supplier JNJ-7706621 genotoxic treatments are strongly discouraged. The present study demonstrates that the apoptotic pathway induced by DRB is independent of ATM and NBS1, namely the proteins defective in AT and the NBS, respec tively. Thus tumours arising in these patients might be efficiently and safely treated with DRB. Moreover, ATM is frequently inactivated in sporadic cancers, particularly lymphoid malignancies, Here, too, DRB could con stitute a very convenient therapeutic option. It could be interesting to evaluate DRB for possible clini cal applications.<br><br> In comparison to other CDK inhibitors already in clinical trials, including flavopiridol 価格 LDN193189 and selici clib, DRB remains one of the most CDK9 selective inhib itors, CDK9 is the kinase with the most specific function limited to regulation of transcription; this selec tivity confers the ability to inhibit pol II phosphorylation rather than cell cycle CDKs or other kinases and to target noncycling cancer cells. Moreover, differently from fla vopiridol that may intercalate into the DNA thereby dam aging it, DRB does not induce DNA damage. Relatively high concentrations of DRB have been used in this work.<br><br> These could perhaps be reduced by combina tion with other drugs if DRB were to be proposed for chemotherapy, since combination of CDK inhibitors, including DRB, with the Mdm2 antagonist, nutlin 3a, leads to the synergistic activation of the cytotoxic p53 functions and allows reduction of the concentrations of both drugs, Similar combinations could be suggested buy LY2228820 to enhance the p53 independent pathways. For example, p53 independent induction of p21Waf1 Cip1 characteris tic of histone deacetylase inhibitors resulted into enhanced cytotoxicity when combined with CDK inhibi tors, Blockade of pol II dependent transcription triggers a cell death signal, though the exact underlying mechanisms were unclear, particularly with respect to its p53 dependence and the need for ongoing DNA replica tion.<br><br> Inhibition of pol II has been found to induce p53 dependent apoptosis associated with trans location of p53 to mitochondria, but only upon entry of cells into S phase or without entry into S phase, yet in a p53 independent way, Our data help to clar ify these issues since we show that in p53 competent cells induction of a transcription independent cytosolic func tion of p53 and subsequent Bax activation are the driving forces of DRB induced apoptosis. This is in accordance with recent data suggesting that blockade of pol II medi ated transcription induced p53 accumulation, and that this is critical for eliciting p53 dependent but transcrip tion independent apoptosis, However, in the absence of p53 DRB efficiently elicits apoptosis through an alternative route that may rely on p73, We also demonstrate that DRB induced apoptosis occurs in G0 G1 cells, without entering into S phase and is thus free from significant DNA replication, and that p53 accumula tion and susequent apoptosis are independent of possible DNA damage as already reported, Our data thus yield new insights into the mechanism of cell death induced by transcriptional blockade.