Abstract
BackgroundTreatment with imatinib mesylate (IM) (a tyrosine kinase inhibitor) is the first line of standard care for patients newly diagnosed with CML. Despite the success of IM and other tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains largely incurable, and a number of CML patients die due to Abl mutation-related drug resistance and blast crisis. 3, 5-Dihydroxy-6, 7, 3′4′-tetramethoxyflavone (DHTMF) is a polymethoxyflavone isolated from Laggera pterodonta which is a herbal medicine used to treat cancer in the Chinese folk. In the previous study, we found DHTMF demonstrated good antiproliferative activities against a number of cancer cell lines and induced the apoptosis of CNE cells in vitro in a time- and dose-dependent manner while exhibiting low cytotoxicity in the two normal cell lines Vero and EVC304. The aim of the present study was to evaluate the proliferation inhibition and apoptosis induced by DHTMF alone and in combination with IM in the IM-resistant CML cell line K562R.MethodsCell proliferation was assayed with the cell counting kit-8 (CCK8) method. The apoptosis percentage was determined by flow cytometry (FCM). Mitochondrial transmembrane potential was detected using FCM and confocal laser-scanning microscopy. The level of proteins involved in apoptosis was detected by Western blotting.ResultsDHTMF suppressed K562R cell viability in both time- and dose-dependent manners. DHTMF combined with IM enhanced the inhibitory effects and apoptosis in K562R cells as compared with DHTMF alone. DHTMF alone and in combination with IM significantly decreased the mitochondrial membrane potential and increased the levels of cleaved caspase-9, caspase-7, caspase-3, and PARP in K562R cells.ConclusionsWe demonstrated that DHTMF could inhibit IM-resistant K562R cell proliferation and induces apoptosis via the intrinsic mitochondrial apoptotic pathway. These results suggest that DHTMF may be a potential therapeutic drug with lower side effects against IM resistance in CML cells.
Highlights
Treatment with imatinib mesylate (IM) is the first line of standard care for patients newly diagnosed with chronic myeloid leukemia (CML)
Effect of DHTMF on cell proliferation We first verified that the IM-resistant K562 cells (K562R) cells we used are IMresistant CML cells
After K562 and K562R cells were treated with different concentrations of IM for 24 h, their cell viability was determined by the cell counting kit-8 (CCK8) assay
Summary
Treatment with imatinib mesylate (IM) (a tyrosine kinase inhibitor) is the first line of standard care for patients newly diagnosed with CML. Despite the success of IM and other tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains largely incurable, and a number of CML patients die due to Abl mutation-related drug resistance and blast crisis. CML prognoses have markedly improved after the introduction of Abl tyrosine kinase inhibitors (TKIs). Despite the increasing success of new TKIs, CML remains largely incurable, and the development of inducible drug resistance is a paramount problem in which patients failed respond to the drugs. How to treat the patients who were resistant to Bcr-Abl tyrosine kinase inhibitors is an important and urgent issue for clinical hematology. More efforts have been directly focused on developing new drugs to control CML with IM resistance
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