MPT0B002, a novel microtubule inhibitor, downregulates T315I mutant Bcr-Abl and induces apoptosis of imatinib-resistant chronic myeloid leukemia cells

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation-mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor. In this study, we evaluated its effects on the proliferation, cell cycle, and apoptosis of K562 CML cells and BaF3 cells expressing either wild-type Bcr-Abl (BaF3/p210) or T315I-mutated Bcr-Abl (BaF3/T315I). MPT0B002 inhibited cell viability in a dose-dependent manner in these cells but did not affect the proliferation of human umbilical vein endothelial cells. It disrupted tubulin polymerization and arrested cell cycle at the G2/M phase. Treatment with MPT0B002 induced apoptosis, and this induction was associated with increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, MPT0B002 can downregulate both Bcr-Abl and Bcr-Abl-T315I mRNA expressions and protein levels and the downstream signaling pathways. Taken together, our findings suggest that MPT0B002 may be considered a promising compound to downregulate not only wild type Bcr-Abl but also the T315I mutant to overcome Bcr-Abl-T315I mutation-mediated resistance in CML cells.

MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

“…We previously showed that MPT0B169 and MPT0B002 are tubulin inhibitors that disrupt tubulin polymerization in leukemia cells [9,10]. Therefore, we examined the effects of MPT0B169 and MPT0B002 on tubulin polymerization in COLO205 and HT29 cells.…”

“…Our previous study showed that MPT0B169 and MPT0B002 can inhibit the proliferation of leukemia cells [9,10]. Herein, to examine the effects of MPT0B169 and MPT0B002 on the cell viability of solid tumor cells, the U87MG and GBM8401 glioblastoma cells, MCF-7 and MDA-MB-231 breast cancer cells, A549 lung cancer cells, COLO205 and HT29 CRC cells were incubated with an increasing concentration of MPT0B169 (0.1-10 μmol/L) or MPT0B002 (0.01-10 μmol/L) for 48 h. Cell viability was determined with an MTT assay.…”

“…MPT0B169 and MPT0B002 were synthesized as previously described [9,10] and dissolved in dimethyl sulfoxide (DMSO; SigmaAldrich, St. Louis, MO, USA).…”

“…1a) [9] and (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002; Fig. 1b) [10] as novel tubulin inhibitors. MPT0B169 inhibited cell growth and arrested cell cycle progression at the G2/M phase in acute myeloid leukemia (AML) cells [9].…”

“…MPT0B169 inhibited cell growth and arrested cell cycle progression at the G2/M phase in acute myeloid leukemia (AML) cells [9]. MPT0B002 induced growth inhibition and apoptosis of chronic myeloid leukemia (CML) cells [10]. However, the effects of MPT0B169 and MPT0B002 on solid tumors have not been examined.…”