Volume 11, Issue 25 of @Oncotarget reported that to examine the role of RSK in AML, the authors analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in Acute Myeloid Leukemia cell lines and patient Acute Myeloid Leukemia cells.
Therefore, the authors investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit.
Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells.
These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.
"Data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit"
Dr. Kathleen M. Sakamoto from Stanford University School of Medicine said, "Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy characterized by the accumulation of immature myeloid blasts with resultant peripheral blood cytopenia."
Treatment of cells with microtubule targeting agents, including paclitaxel and the vinca alkaloid vincristine, blocks the proper formation of the mitotic spindle through inhibition of microtubule dynamics, resulting in the prolonged mitotic arrest of cancer cells.
MTAs-treated mitotic arrested cells may undergo apoptosis in mitosis, however, the rapid degradation of Cyclin B due to an insufficient SAC leads to the mitotic slippage into tetraploid G1 stage in resistant cells.
Though vinca alkaloid microtubule-destabilizing compounds have shown clinical efficacy against various hematological malignancies and were included in combination chemotherapy of the VAPA study, they are not currently used in induction chemotherapy for AML due to their high toxicity against lymphoid cells and rapid degradation by myeloperoxidase in AML cells.
Figure 8: BI-D1870 in combination with vincristine increase metaphase arrest and apoptosis synergistically. (A, B) Cell cycle distribution of HL60 and Nalm6 cells treated with BI-D1870 and vincristine. Cells were treated with BI-D1870 (2.5 μM) and/or vincristine (5 nM) for 1 d, and then cells were fixed and analyzed for cell cycle distribution. Cells were stained with 4,6-diamidino-2-phenylindole (DAPI) and antibodies. Percentages of live cell populations at each cell cycle phase determined by DNA content (DAPI) and levels of p-H3, Cyclin A, and Cyclin B were graphed. (C) Cells were treated with BI-D1870 (2.5 μM) and/or vincristine (5 nM) for 1d or 2d. Percentages of Annexin V-positive apoptotic cells are calculated. (D) Synergistic combination effect of BI-D1870 and vincristine. Cells were treated with various concentrations of BI-D1870 and vincristine for 3d. Viability was assessed using the CellTiter glo assay kit. The combination index (CI) values were calculated by the Chou-Talalay method using CalcuSyn software. CI > 1: antagonism, CI = 1: additive Effect, CI < 1: synergism. Data are the mean ± SEM (n = 4). (E) BI-D1870 in combination with vincristine-induced apoptosis synergistically in primary patient AML cells. Primary cells were treated with BI-D1870 (1.5 μM) and/or vincristine (3 nM) for 2d, and then Annexin V-positive cells were assessed using flow cytometry. Data are graphed as mean ± SEM (n = 3). **p < 0.01; ***p < 0.001. (F) A proposed action model of the RSK inhibitor BI-D1870 in mitotic exit. BI-D1870 inhibits the disassembly of the MCC to activate APC/C for anaphase transition by blocking the phosphorylation-induced conformation change of MAD2.
In this study, they demonstrate that BI-D1870, a potent inhibitor of RSK, induces mitotic arrest, and apoptosis in AML cells without inhibiting CDC2 and CDC25C. Furthermore, BI-D1870 synergizes with vinca alkaloid vincristine in AML cells, suggesting that inhibition of mitotic exit with BI-D1870 could be a promising novel approach for AML therapy in combination with MTAs.
The Sakamoto Research Team concluded in their Oncotarget Research Paper that BI-D1870 is a reversible pan-RSK inhibitor, showing > 500-fold higher activity for RSK than other AGC kinases.
BI-D1870 also inhibits the activity of PLK1, Aurora-B, MELK, PIM3, MST2, and GSK3β at higher concentrations than for RSK. BI-D1870 and BRD7389 have been reported to inhibit proliferation and significantly increase the G2/M population in melanoma cells.
BI-D1870 does not have proper physicochemical properties for clinical application.
Future structure-activity relationships study for BI-D1870 is required to improve solubility and pharmacokinetic profiles for in vivo preclinical and clinical studies.
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DOI - https://doi.org/10.18632/oncotarget.27630
Full text - https://www.oncotarget.com/article/27630/text/
Correspondence to - Kathleen M. Sakamoto - [email protected]
Keywords - acute myeloid leukemia, BI-D1870, RSK, vincristine, spindle assembly checkpoint
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