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Enhanced Antitumor Activity by the Combination of Dasatinib and Selinexor in Chronic Myeloid Leukemia

Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the poten...

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Main Authors: Mariarita Spampinato (Author), Tatiana Zuppelli (Author), Ilaria Dulcamare (Author), Lucia Longhitano (Author), Domenico Sambataro (Author), Annalisa Santisi (Author), Amer M. Alanazi (Author), Ignazio A. Barbagallo (Author), Nunzio Vicario (Author), Rosalba Parenti (Author), Alessandra Romano (Author), Giuseppe Musumeci (Author), Giovanni Li Volti (Author), Giuseppe A. Palumbo (Author), Francesco Di Raimondo (Author), Anna Nicolosi (Author), Sebastiano Giallongo (Author), Vittorio Del Fabro (Author)
Format: Book
Published: MDPI AG, 2024-07-01T00:00:00Z.
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Summary:Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. Methods: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. Results: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. Conclusions: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.
Item Description:10.3390/ph17070894
1424-8247

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