Hammada scoparia flavonoids and rutin kill adherent and chemoresistant leukemic cells
Introduction
Acute myeloid leukemia (AML) is characterized by the aberrant accumulation of immature myeloid hematopoietic cells. The leukemia-initiating cells are hematopoietic stem cells which have either dysregulated self-renewal and differentiation functions or have committed progenitors transformed to leukemic stem cells (LSCs). Current chemotherapy for AML uses drugs such as nucleoside analogs and anthracyclines that interfere with DNA replication and induce apoptosis primarily in replicating cells. However, since LSCs are mostly quiescent like hematopoietic stem cells (HSCs) [1], relapse is common after initial remission in response to chemotherapy.
The hematopoietic niche plays a key role in maintaining HSCs quiescence. Adhesive interactions between HSCs and their microenvironment are required to maintain stem cell capacities. We and others have demonstrated that adhesive interactions, notably through integrin engagement on fibronectin, are responsible for cell adhesion-mediated drug resistance (CAM-DR) of leukemic cells [2]. Current research is focussing on determining specific cell survival mechanisms that distinguish LSCs from HSCs in order to develop LSC-specific targeted therapy.
Nuclear factor κB (NF-κB) and mammalian target of rapamycin (mTOR) were found overactivated in LSCs and have been proposed as targets for LSCs therapy [3], [4]. The phosphoinositide 3-kinase/Akt pathway regulates NF-κB and mTOR activities, and has been shown to mediate CAM-DR of AML [5]. Another key signaling molecule controlling the NF-κB and mTOR pathways is the glycogen synthase kinase 3β (GSK3β), a serine threonine kinase important for survival responses to various extracellular stress from the microenvironment [6]. Interestingly, GSK3β activation is linked to a cell quiescence status and regulates specifically NF-κB allowing the transcription of genes such as IL-6, a cytokine involved in the survival of malignant hematopoietic cells [7].
We have previously demonstrated that GSK3β activation supports CAM-DR [2] and resistance to TNF-α [8] of leukemic blasts. Having obtained preliminary results showing that aqueous extracts from Hammada scoparia had anti-inflammatory properties correlated with GSK3β downregulation in a rat model of hepatotoxicity (Bourogaa et al., in preparation), we raised the question of putative modulation of leukemic cell survival by H. scoparia compounds. H. scoparia is a medicinal plant whose anti-cancer, anti-inflammatory and anti-oxidant properties, as well as phytochemistry, are little known [9]. In this work, we tested the activity of H. scoparia extracts over leukemic or normal hematopoietic cells and identified one of the bioactive components as rutin.
Section snippets
Cells
Leukemic cell lines U937, HL-60, KG1 and KG1a were purchased from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and grown as previously described [8]. AML cells were obtained from bone marrow of six patients with informed consent at diagnostic, using Ficoll-Hypaque density-gradient centrifugation (Collection No. 1 HIMIP AC-2008-129/DC-2008-307 approved by CCPRB, Toulouse University Hospital Dr. C. Demur). Bone marrow samples contained more than 80% leukemic
Aqueous extracts and flavonoid-enriched fractions from H. scoparia are cytotoxic for leukemic cells
Aqueous extracts were prepared from dried H. scoparia leaves and serial dilutions were assayed for cytotoxic effects on leukemic cells either in suspension or in adhesion. As shown in Fig. 1A, pretreatment of U937 leukemic cells with aqueous extract from H. scoparia (EtOH/H2O 1:9, v/v) reduced survival of adherent U937 (30% decrease of survival). The survival of leukemic cells in suspension was slightly affected. The cytotoxic effects of DNR were strongly increased by the H. scoparia aqueous
Discussion
Natural plant extracts and their flavonoids have been shown to display anti-cancer properties both in vitro and in vivo. Clinical trials with flavonoids have been performed for their development as anti-leukemic agents [17], [18], [19], [20]. Here, we have demonstrated that H. scoparia flavonoids and rutin have the capacity to specifically induce the cytotoxicity of adherent and chemoresistant leukemic progenitors.
Cytotoxic assays with flavonoids glycosides present in H. scoparia, or
Conflict of interest
All authors have no conflict of interest to declare.
Acknowledgements
The authors would thank Drs M. Allouche, A. Gargouri and C. Cambon for helpful discussion along the realization of this work. The orthopedic service of CHU Purpan (Toulouse, France) and Pr. P. Bonnevialle are greatly acknowledged for providing human bone fragments. The authors would thank also the «plateforme de cytométrie» in IFR150.
Funding source: Association de Recherche contre le Cancer (contracts no. 3638 and 8407), Institut National du Cancer (contract no. 07/3D1616/IABC-23-8/NC-NG),
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Thermodynamic and structural description of relative solubility of the flavonoid rutin by DFT calculations and molecular dynamics simulations
2021, Journal of Molecular LiquidsCitation Excerpt :Similarly, [22] found that rutin significantly decreased the migration of human A549 cells (lung cancer) [22]. These and other properties have attracted the attention of researchers for the rutin and other flavonoids [23–26]. The chemical structure of the rutin is shown in Fig. 1, together with the thirty-second rutin geometry of our recent conformational analysis, based on Density Functional Theory (DFT) [27] calculations of thermodynamic and spectroscopic properties [28].
Rutin prevents cisplatin-induced ovarian damage via antioxidant activity and regulation of PTEN and FOXO3a phosphorylation in mouse model
2020, Reproductive ToxicologyCitation Excerpt :These results can be related to the antioxidant effects of the rutin like inhibition of ROS generation, increase in the activity of antioxidant enzymes, such as glutathione (GSH), and prevention of lipid peroxidation, attenuating DNA and mitochondrial damage [21–23]. Rutin actions can be regulated by phosphatidylinositol 3-kinase (PI3K) signaling pathway members, which are important for the maintenance of cell survival and growth, such as phosphatase and tension homolog (PTEN) and Forkhead box O3 (FOXO3a) [24–27]. PTEN phosphorylation can effectively inhibit cell proliferation and induce apoptosis [28], while down-regulation of phosphorylated PTEN (p-PTEN) induces PI3K activation and consequent FOXO3a phosphorylation (p-FOXO3a), increasing its nuclear export, which promotes follicle activation and/or decreases apoptosis [29–31].
Rutin- serum albumin interaction in different media and its effective dose selection in radiation-induced cytotoxicity on human blood cells
2020, Journal of Herbal MedicineCitation Excerpt :DNA protective action of rutin has also been demonstrated (Marcarini et al., 2011). Rutin also has an inhibitory effect on the survival of leukemic progenitor cells (Bourogaa et al., 2011) and has been shown to inhibit inflammatory responses in UVB-irradiated mouse skin by inhibiting the increase in phosphorylated levels of STAT3; p38 MAPK and JNK (Choi et al., 2014; Perk et al., 2014). All these findings support the beneficial biological actions of rutin regarding its anticancer and anti-inflammatory responses with significant information about the signaling pathway involved.