Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Abstract

Aim: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. Methods: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. Results: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC 50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC 50 at low micromole levels. C817 (0.5 or 1 μmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. Conclusion: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.

Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells

“…In contrast, many flavonoids have been shown to induce cell death through induction of autophagy. For example, curcumin is able to induce both autophagy and apoptosis in chronic myeloid leukemia cells via downregulation of the Bcl-2 protein 33 . Quercetin induces extensive autophagy in epithelial cancer cells, which led to cell cycle arrest and induction of apoptosis 34 , etc.…”

Curcumin inhibitsin vitroandin vivochronic myelogenous leukemia cells growth: a possible role for exosomal disposal of miR-21

“…Curcumin is a promising compound that in association with classical tyrosine kinase inhibitor, may improve the treatment of CML patients resistant to Imatinib, the election drug for this leukemia [ 24 ]. In this study, we show in in vitro and in vivo models that treatment of CML cells with Curcumin caused a miR-21-mediated modulation of PTEN/AKT pathway leading to the inhibition of leukemic cell growth.…”

A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe

“…In fact, curcumin has shown to inhibit the growth, as well as metastases in several tumor derived cell lines [11]. In addition, a curcumin derivative induces apoptosis in treatment resistant chronic myelogenous leukemia [12]. In a previous study, a mouse model of myelogenous progenitor cells with exogenous expression of the BCR-ABL chimeric gene in the 32D cells was assessed, and 20 μM of curcumin produced cell cycle arrest in the G2/M phase, as well as changes in nuclear morphology typical of mitotic catastrophe.…”