Journal Article Epublish
PubMed: 40149555 DOI: 10.3390/biomedicines13030578
Sonidegib Inhibits the Adhesion of Acute Myeloid Leukemia to the Bone Marrow in Hypoxia: An Optical Tweezer Study.
Biomedicines 13(3)
Authors: Katarzyna Gdesz-Birula, Sławomir Drobczyński, Krystian Sarat, Kamila Duś-Szachniewicz
Affiliations
- Department of Clinical and Experimental Pathology, Institute of General and Experimental Pathology, Wrocław Medical University, 50-368 Wrocław, Poland.
- Department of Optics and Photonics, Faculty of Fundamental Problems of Technology, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wrocław, Poland.
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia cells by promoting pro-survival signaling pathways and drug resistance. Therefore, attenuating interactions between leukemia cells and BM cells may have a positive therapeutic effect. In this work, we hypothesized that sondages may inhibit the adhesion of leukemia cells to the bone marrow by inhibiting the Hedgehog (Hh) signaling pathway. The Hedgehog pathway is a key therapeutic target in AML due to its role in leukemic cell growth and survival. We investigated the effects of sonidegib on the adhesion of individual OCI-AML3 cells to a bone marrow stromal spheroid derived from the HS-5 cell line. For this purpose, we precisely determined the minimum cell-to-cell adhesion time using optical tweezers under normoxic (21% of O) and hypoxic (1% of O) conditions. Our results demonstrated that sonidegib significantly increased the minimum cell-to-cell adhesion time necessary for leukemic cells to establish adhesive bonds with bone marrow stromal cells, thereby indicating a reduction in their adhesive properties. Additionally, we showed that sonidegib is particularly effective at hypoxic oxygen concentrations. The results obtained in this study suggest that sonidegib, through its modulation of the Hedgehog signaling pathway, holds promise as a potential therapeutic approach to target leukemic cell adhesion within the bone marrow microenvironment.
MeSH
Cells, Tissue Adhesions, Bone Marrow, Leukemia, Leukemia, Myeloid, Acute, Leukemia, Myeloid, Cell Adhesion, Hypoxia, Adhesives, Therapeutics, Stromal Cells