Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB. was written by Buontempo, Francesca;Orsini, Ester;Lonetti, Annalisa;Cappellini, Alessandra;Chiarini, Francesca;Evangelisti, Camilla;Evangelisti, Cecilia;Melchionda, Fraia;Pession, Andrea;Bertaina, Alice;Locatelli, Franco;Bertacchini, Jessika;Neri, Luca Maria;McCubrey, James A;Martelli, Alberto Maria. And the article was included in Oncotarget in 2016.Recommanded Product: 1009820-21-6 This article mentions the following:
The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL. In the experiment, the researchers used many compounds, for example, 5-((3-Chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid (cas: 1009820-21-6Recommanded Product: 1009820-21-6).
5-((3-Chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid (cas: 1009820-21-6) belongs to naphthyridine derivatives. The naphthyridines have 10 delocalized π-electrons located in five molecular orbitals, each of which is distorted by the presence of the nitrogen atoms causing an electron drift in that direction. 1,6-Naphthyridine and some of its derivatives have been reported to have medicinal, electronic, and catalytic properties. But none of these investigations has yet resulted in any practical applications. Very few metal complexes of naphthyridines other than 1,8-naphthyridine have been described.Recommanded Product: 1009820-21-6
Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem