PMID- 38396682 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240227 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 25 IP - 4 DP - 2024 Feb 7 TI - Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance. LID - 10.3390/ijms25041994 [doi] LID - 1994 AB - 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. FAU - Bistue-Rovira, Angel AU - Bistue-Rovira A AD - Departament de Farmacologia, Terapeutica i Toxicologia, Universitat Autonoma de Barcelona (UAB), 08193 Cerdanyola del Valles, Spain. FAU - Rico, Laura G AU - Rico LG AUID- ORCID: 0000-0001-9867-4393 AD - Germans Trias i Pujol Research Institute (IGTP), Universitat Autonoma de Barcelona (UAB), 08916 Badalona, Spain. FAU - Bardina, Jorge AU - Bardina J AD - Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain. FAU - Junca, Jordi AU - Junca J AD - MDS Group, Institut de Recerca Contra la Leucemia Josep Carreras, 08916 Badalona, Spain. FAU - Granada, Isabel AU - Granada I AD - MDS Group, Institut de Recerca Contra la Leucemia Josep Carreras, 08916 Badalona, Spain. FAU - Bradford, Jolene A AU - Bradford JA AD - Thermo Fisher Scientific, Fort Collins, CO 80524, USA. FAU - Ward, Michael D AU - Ward MD AD - Thermo Fisher Scientific, Fort Collins, CO 80524, USA. FAU - Salvia, Roser AU - Salvia R AUID- ORCID: 0000-0002-2118-9231 AD - Germans Trias i Pujol Research Institute (IGTP), Universitat Autonoma de Barcelona (UAB), 08916 Badalona, Spain. FAU - Sole, Francesc AU - Sole F AUID- ORCID: 0000-0002-3251-2161 AD - MDS Group, Institut de Recerca Contra la Leucemia Josep Carreras, 08916 Badalona, Spain. FAU - Petriz, Jordi AU - Petriz J AD - Germans Trias i Pujol Research Institute (IGTP), Universitat Autonoma de Barcelona (UAB), 08916 Badalona, Spain. LA - eng GR - NA/CERCA Institution/ GR - NA/Thermo Fisher Scientific (Norway)/ PT - Journal Article DEP - 20240207 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - IT942ZTH98 (Curcumin) RN - 1X70OSD4VX (ibrutinib) RN - P2K93U8740 (fludarabine) RN - JAC85A2161 (Adenine) RN - 0 (Piperidines) RN - FA2DM6879K (Vidarabine) SB - IM MH - Humans MH - *Leukemia, Lymphocytic, Chronic, B-Cell/metabolism MH - *Curcumin/pharmacology/therapeutic use MH - Tetraploidy MH - Adenine/*analogs & derivatives MH - *Piperidines MH - Vidarabine/*analogs & derivatives PMC - PMC10888954 OTO - NOTNLM OT - CLL OT - LSCs OT - alkaline phosphatase OT - curcumin OT - flow cytometry OT - stem-like COIS- M.D.W. and J.A.B. work for Thermo Fisher Scientific, which is in the business of selling flow cytometers and flow cytometry reagents. The rest of authors declare no potential conflicts of interest. EDAT- 2024/02/24 11:46 MHDA- 2024/02/26 06:44 PMCR- 2024/02/07 CRDT- 2024/02/24 01:02 PHST- 2023/11/20 00:00 [received] PHST- 2024/01/11 00:00 [revised] PHST- 2024/01/25 00:00 [accepted] PHST- 2024/02/26 06:44 [medline] PHST- 2024/02/24 11:46 [pubmed] PHST- 2024/02/24 01:02 [entrez] PHST- 2024/02/07 00:00 [pmc-release] AID - ijms25041994 [pii] AID - ijms-25-01994 [pii] AID - 10.3390/ijms25041994 [doi] PST - epublish SO - Int J Mol Sci. 2024 Feb 7;25(4):1994. doi: 10.3390/ijms25041994.