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Advancing the Therapeutic Effectiveness of Paclitaxel in Chronic Lymphocytic Leukemia Through the Simultaneous Inhibition of Notch1 and Sf3b1 Publisher



Abolhasani S1 ; Salehi Khesht AM1 ; Khodakarami A2 ; Masjedi A3, 4 ; Rashidi B1 ; Izadi S5 ; Noukabadi FK1 ; Karpisheh V1 ; Poudeh KT1 ; Jalali P6 ; Salehi Z7 ; Bagherifar R2 ; Hejazian SS1 ; Movassaghpour A8 Show All Authors
Authors
  1. Abolhasani S1
  2. Salehi Khesht AM1
  3. Khodakarami A2
  4. Masjedi A3, 4
  5. Rashidi B1
  6. Izadi S5
  7. Noukabadi FK1
  8. Karpisheh V1
  9. Poudeh KT1
  10. Jalali P6
  11. Salehi Z7
  12. Bagherifar R2
  13. Hejazian SS1
  14. Movassaghpour A8
  15. Feizi AAH9
  16. Jadidi F1, 9
Show Affiliations
Authors Affiliations
  1. 1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  2. 2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, 81675, Germany
  4. 4. Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, 81675, Germany
  5. 5. Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
  6. 6. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  9. 9. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Source: Cancer Cell International Published:2025


Abstract

Background: Chemoresistance is still a significant obstacle to cancer therapy. Overexpression of the splicing factor 3b subunit 1 (SF3B1) and neurogenic locus notch homolog protein 1 (NOTCH1) factors is typically found in chronic lymphocytic leukemia (CLL), leading to the development of chemotherapy resistance. Objective: The current investigation aims to evaluate the chemosensitivity of CLL cells by blocking NOTCH1 and SF3B1 using chitosan lactate (CL) nanoparticles (NPs). Methods: We used CL-NPs loaded with anti-NOTCH1 and -SF3B1 small interfering RNAs (siRNAs) in combination with paclitaxel (PTX) to suppress NOTCH1 and SF3B1 in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) isolated from CLL cases to assess the impact of this therapeutic strategy on leukemic cell chemosensitivity. Further, the competing endogenous RNA (ceRNA) network that regulates NOTCH1 and -SF3B1 was constructed and enriched. Results: Our findings showed that CL-NPs loaded with anti-NOTCH1/-SF3B1 siRNAs-PTX significantly suppressed NOTCH1 and SF3B1 expression in PBMCs and BMMCs isolated from CLL cases in comparison with the untreated samples, leading to increased leukemic cell sensitivity to PTX and decreased the proliferative capacity of leukemic cells. The enrichment analysis highlighted the fundamental pathways where the NOTCH1- and SF3B1-associated ceRNA network exerts its influence in the context of CLL. Conclusions: This study implies the efficacy of combined therapy by CL-NPs loaded with anti-NOTCH1/-SF3B1 siRNAs and PTX as a novel therapeutic strategy for CLL, even though further studies are required to warrant the findings. © The Author(s) 2025.
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