Cannabidiol modulates exosomal miRNA networks to enhance Imatinib mesylate response in chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease driven by the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKIs) such as Imatinib mesylate have dramatically improved patient outcomes, yet resistance remains a major obstacle to long-term efficacy. Exosomes, as carriers of bioactive molecules including miRNAs, are increasingly recognized as mediators of drug resistance. CBD has demonstrated antiproliferative and pro-apoptotic effects in several cancer models, but its potential to modulate Imatinib sensitivity or resistance in CML remains unclear. This study aimed to investigate exosomal miRNA signatures associated with Imatinib sensitivity and resistance in the context of treatment with Cannabidiol (CBD), Imatinib mesylate (IM), and their combination.

Following treatment with CBD, IM, and CBD+IM, exosomal miRNA profiles in Imatinib-sensitive (K-562S) and Imatinib-resistant (K-562 R) cell lines were analyzed. Gene Ontology (GO) enrichment and semantic clustering was performed.

CBD activated tumor-suppressive and apoptosis-related miRNAs in K-562S cells, whereas K-562 R cells showed a dual response involving oncogenic miRNAs and metabolic regulators. IM induced suppressive cascades in K-562S but caused loss of canonical tumor suppressors in K-562 R. CBD+IM produced synergistic amplification of apoptotic and differentiation-related pathways in sensitive cells, while resistant cells showed partial restoration of apoptosis but persistent loss of tumor suppressors. HMGB1-associated miRNAs were identified, of which suppressed were miR-615-5p, miR-4435, let-7 g-3p, and the miR-548 family, alongside upregulated miR-3191-3p and miR-33a-5p.

Circulating miRNAs are valuable biomarkers for TKI resistance in CML. Targeting HMGB1-associated miRNAs, together with combined CBD and IM treatment, may help re-establish apoptotic regulation and overcome resistance mechanisms.