Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells

• Published in: Biological & pharmaceutical bulletin Vol. 43; no. 10; pp. 1526 - 1533
• Main Authors: Wang, Xin-Yi, Sun, Gui-Bin, Wang, Ya-Jing, Yan, Fang
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.10.2020; Japan Science and Technology Agency
• Subjects: Abl protein; allosteric inhibition; Allosteric properties; Apoptosis; Bcl-2 protein; BCR protein; Binding sites; breakpoint cluster region-abelson tyrosine kinase; c-Myc protein; Caspase-3; Cell proliferation; Chronic myeloid leukemia; Emodin; Fusion protein; Glycoproteins; Imatinib; imatinib-resistance; Leukemia; Mcl-1 protein; Multidrug resistance; Myc protein; Myeloid leukemia; P-Glycoprotein; Phosphorylation; Poly(ADP-ribose) polymerase; Ribose; signal transducer and activator of transcription 5; Stat5 protein; Targeted cancer therapy; Transcription factors
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b20-00325

Imatinib-resistance is a significant concern for Bcr-Abl-positive chronic myelogenous leukemia (CML) treatment. Emodin, the predominant compound of traditional medicine rhubarb, was reported to inhibit the multidrug resistance by downregulating P-glycoprotein of K562/ADM cells with overexpression of P-glycoprotein in our previous studies. In the present study, we found that emodin can be a potential inhibitor for the imatinib-resistance in K562/G01 cells which are the imatinib-resistant subcellular line of human chronic myelogenous leukemia cells with overexpression of breakpoint cluster region-abelson (Bcr-Abl) oncoprotein. Emodin greatly enhanced cell sensitivity to imatinib, suppressed resistant cell proliferation and increased potentiated apoptosis induced by imatinib in K562/G01 cells. After treatment of emodin and imatinib together, the levels of p-Bcr-Abl and Bcr-Abl were significantly downregulated. Moreover, Bcr-Abl important downstream target, STAT5 and its phosphorylation were affected. Furthermore, the expression of Bcr-Abl and signal transducers and activators of transcription 5 (STAT5) related molecules, including c-MYC, MCL-1, poly(ADP-ribose)polymerase (PARP), Bcl-2 and caspase-3, were changed. Emodin also decreased Src expression and its phosphorylation. More importantly, emodin simultaneously targeted both the ATP-binding and allosteric sites on Bcr-Abl by molecular docking, with higher affinity with the myristoyl-binding site for enhanced Bcr-Abl kinase inhibition. Overall, these data indicated emodin might be an effective therapeutic agent for inhibiting resistance to imatinib in CML treatment.