2026-04-13T02:07:22Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/125762025-10-24T10:25:27Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Bistué Rovira, Àngel author Garcia Rico, Laura author Junca, Jordi author Granada, Isabel author Bradford, Jolene A. author Bardina Santos, Jorge author 2025-02-10T13:38:14Z 2025-02-10T13:38:14Z 2024-02-07 Alkaline phosphatase; Curcumin; Flow cytometry Fosfatasa alcalina; Curcumina; Citometria de flux Fosfatasa alcalina; Curcumina; Citometría de flujo Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy. Grant Sponsor: Thermo Fisher Scientific, Eugene, Oregon, USA. Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain (PI/17/0575 and PI 20/00531, co-funded by European Regional Development Fund. ERDF, a way to build Europe); CERCA, Centres de Recerca de Catalunya (2021 SGR 00560; 2021 SGR 00002); La Caixa Foundation, Obra Social la Caixa, Fundació Internacional Josep Carreras, Barcelona, Spain. http://hdl.handle.net/11351/12576 Leucèmia limfocítica crònica - Tractament Medicaments antineoplàstics - Ús terapèutic Proteïnes quinases - Inhibidors - Ús terapèutic Resistència als medicaments PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols DISEASES::Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell Other subheadings::Other subheadings::Other subheadings::/drug therapy CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada ENFERMEDADES::enfermedades hematológicas y linfáticas::enfermedades linfáticas::trastornos linfoproliferativos::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance