Advancing the therapeutic effectiveness of paclitaxel in chronic lymphocytic leukemia through the simultaneous inhibition of NOTCH1 and SF3B1

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. Graphical abstract