Search

Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in granulocyte–macrophage progenitors, and highest among a novel CD34+CD38+CD123hiTim-3hisubset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells. A novel Wnt/β-catenin signaling modulator, C82, and nilotinib synergistically killed KBM5T315Iand TKI-resistant primary BC-CML cells with or without BCR–ABL kinase mutations even under leukemia/MSC co-culture conditions. Silencing of β-catenin by short interfering RNA restored sensitivity of primary BCR–ABLT315I/E255VBC-CML cells to nilotinib. Combining the C82 pro-drug, PRI-724, with nilotinib significantly prolonged the survival of NOD/SCID/IL2Rγ null mice injected with primary BCR–ABLT315I/E255VBC-CML cells. The combined treatment selectively targeted CML progenitors and inhibited CD44, c-Myc, survivin, p-CRKL and p-STAT5 expression. In addition, pretreating primary BC-CML cells with C82, or the combination, but not with nilotinib alone, significantly impaired their engraftment potential in NOD/SCID/IL2Rγ-null-3/GM/SF mice and significantly prolonged survival. Our data suggest potential benefit of concomitant β-catenin and Bcr–Abl inhibition to prevent or overcome Bcr–Abl kinase-dependent or -independent TKI resistance in BC-CML.

‘Dang‐Gui Decoction for Enriching the Blood’ (BE), a traditional Chinese formulation comprising Angelica sinensisand Astragalus membranaceus, is used for stimulating red blood cell production as well as enhancing cardiovascular function. In the present study, we have demonstrated the myocardial protection afforded by BE pretreatment against ischaemia‐reperfusion (IR) injury in isolated‐perfused rat hearts. A more complete and potent myocardial protection against IR injury was also shown by a Polygonum multiflorumextract supplemented BE preparation (BEA). The results suggest that the more potent cardioprotective action of BEA may be related to its ability to sustain the myocardial glutathione antioxidant status under conditions of IR‐induced oxidative stress, which may possibly in turn result from the synergistic interaction between the BE and Polygonum extract. Copyright © 2000 John Wiley & Sons, Ltd.

‘Dang-Gui Decoction for Enriching the Blood’ (BE), a traditional Chinese formulation comprising Angelica sinensis and Astragalus membranaceus, is used for stimulating red blood cell production as well as enhancing cardiovascular function. In the present study, we have demonstrated the myocardial protection afforded by BE pretreatment against ischaemia-reperfusion (IR) injury in isolated-perfused rat hearts. A more complete and potent myocardial protection against IR injury was also shown by a Polygonum multiflorum extract supplemented BE preparation (BEA). The results suggest that the more potent cardioprotective action of BEA may be related to its ability to sustain the myocardial glutathione antioxidant status under conditions of IR-induced oxidative stress, which may possibly in turn result from the synergistic interaction between the BE and Polygonum extract. Copyright © 2000 John Wiley & Sons, Ltd.