XMU-MP-1, the Hippo Signaling Pathway MST-1 Kinase Inhibitor, Prevents the Development of Drug Resistance to Doxorubicin in Hematological Tumor Cells.

Background/

Objectives

The search for new drugs which could suppress drug resistance development in tumor cells is extremely important for clinical practice. Inhibitors of cell signaling pathways that control cell proliferation and death can be used in complex therapy of malignant tumors.

Methods

Cell cycle assay using flow cytometry, In Vitro Cell Viability Assay Cell chemosensitivity was analyzed by direct cell counting after trypan blue staining using a microscope.

Results

In the present work, we have shown that the combined action of doxorubicin and XMU-MP-1, the MST1/2 kinase inhibitor in the Hippo signaling pathway, prevents drug resistance development in Namalwa cells, significantly slows drug resistance development in K562 cells, and restores the sensitivity of resistant K562 cells to doxorubicin. We have shown that compared to monotherapy, the combination of doxorubicin and XMU-MP-1 causes a significant decrease in cell division rate and cell death in hematological tumor cells such as Burkitt's lymphoma Namalwa and chronic myeloid leukemia (CML) K562 cells. Cell cycle analysis revealed that the combined action of XMU-MP-1 and doxorubicin caused a catastrophic cell cycle disruption and a significant increase in the number of cells undergoing apoptosis containing fragmented DNA.

Conclusions

XMU-MP-1 can be potentially used in combination with anthracyclines for the treatment of hematological malignancies and, in particular, drug-resistant cancer types.