Jun Young Heo
Chungnam National University, South Korea
Title: Synergistic Bcr/Abl degradation effect is triggered by MB12066 with NQO2 inhibitors in chronic myelogenous leukemia
Biography
Biography: Jun Young Heo
Abstract
Mutations of Bcr-Abl protein reduce the sensitivity of imatinib treatment for chronic myelogenous leukemia (CML). The resistance against imatinib treatment to CML patients needs to develop another target drug of Bcr-Abl through unknown mechanism. In present study, we investigated the effect of MB12066, small molecule related to quinone derivatives, on k562 cells (CML cell line) and the expression level of Bcr-Abl protein down regulated by MB12066. When k562cells were treated with MB12066, dose-and time-dependent Bcr-Abl degradation was detected, followed by decreasing of procaspase-3 and cleavage of PARP, which represent apoptotic stimuli. Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1(NQO1) and NRH:quinone oxidoreductase2 (NQO2)] are the major enzymes involved in the bioreduction of quinone-containing drugs. We found that MB12066 was a substrate of both NQO1 and NQO2 by examining recycling assay. For the functional study of NQO1 and NQO2 in Bcr-Abl degradation, we used inhibitors for each enzymes, dicumarol and quercetin, respectively. Interestingly, Bcr-Abl degradation was inhibited by dicumarol, but it was accelerated by quercetin. Collectively, these results demonstrate that MB12066 destruct the Bcr-Abl through the NQO1 and NQO2 activity and it may show the possibility that combination therapy with NQO2 inhibitor may be beneficial for treating CML patients.