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  • Eriksson, Anna, et al. (författare)
  • Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia
  • 2015
  • Ingår i: Blood Cancer Journal. - 2044-5385 .- 2044-5385. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.
  • Eriksson, Anna, 1977-, et al. (författare)
  • Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.
  • 2017
  • Ingår i: Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis. - 0145-2126 .- 1873-5835. ; 63, s. 41-46
  • Tidskriftsartikel (refereegranskat)abstract
    • We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.
  • Fakhoury, Isabelle, et al. (författare)
  • Uptake, delivery, and anticancer activity of thymoquinone nanoparticles in breast cancer cells
  • 2016
  • Ingår i: Journal of nanoparticle research. - 1388-0764 .- 1572-896X. ; 18:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Thymoquinone (TQ) is a promising anticancer molecule but its development is hindered by its limited bioavailability. Drug encapsulation is commonly used to overcome low drug solubility, limited bioavailability, and nonspecific targeting. In this project, TQ nanoparticles (TQ-NP) were synthesized and characterized. The cytotoxicity of the NP was investigated in nontumorigenic MCF-10-A breast cells, while the uptake, distribution, as well as the anticancer potential were investigated in MCF-7 and MDA-MB-231 breast cancer cells. Flash Nanoprecipitation and dynamic light scattering coupled with scanning electron microscopy were used to prepare and characterize TQ-NP prior to measuring their anticancer potential by MTT assay. The uptake and subcellular intake of TQ-NP were evaluated by fluorometry and confocal microscopy. TQ-NP were stable with a hydrodynamic average diameter size around 100 nm. Entrapment efficiency and loading content of TQ-NP were high (around 80 and 50 %, respectively). In vitro, TQ-NP had equal or enhanced anticancer activity effects compared to TQ in MCF-7 and aggressive MDA-MB-231 breast cancer cells, respectively, with no significant cytotoxicity of the blank NP. In addition, TQ and TQ-NP were relatively nontoxic to MCF-10-A normal breast cells. TQ-NP uptake mechanism was both time and concentration dependent. Treatment with inhibitors of endocytosis suggested the involvement of caveolin in TQ-NP uptake. This was further confirmed by subcellular localization findings showing the colocalization of TQ-NP with caveolin and transferrin as well as with the early and late markers of endocytosis. Altogether, the results describe an approach for the enhancement of TQ anticancer activity and uncover the mechanisms behind cell-TQ-NP interaction.
  • Forslund, Marina (författare)
  • A nutrition intervention in men with prostate cancer Exploring effects on bowel symptoms from radiotherapy, patient experience, and nutrient intake
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Objective The main objective of this thesis was to explore the effects of a nutrition intervention on acute and late bowel symptoms in men with localised prostate cancer treated with pelvic radiotherapy (study I), participants’ experiences from receiving the nutrition intervention (study II), and associations with nutrient intakes (study III).Methods A total of 180 men with localised prostate cancer referred to curative radiotherapy targeting the prostate gland and pelvic lymph nodes were recruited to the trial. The participants were randomised to standard care plus a nutrition intervention aiming to modify fibre and lactose intakes (NIG; n=92) or standard care alone (SCG; n=88). Data on bowel symptoms and dietary intake were collected pre-treatment and at seven time points during a 26-month study period. Analyses of the effects of the nutrition intervention on bowel symptoms were conducted for the acute phase (up to 2 months post radiotherapy), and the late phase (7 to 24 months post radiotherapy). Semi-structured interviews were conducted with 15 participants from the NIG to explore experiences of the nutrition intervention.Results The nutrition intervention was associated with statistically significantly, but not clinically significantly, less bother from blood in stools and flatulence during the acute phase. The nutrition intervention was also associated with more bloated abdomen during the late phase (Study I). Social support, contributing to the greater good, prior knowledge, dietary information, and a small need for change facilitated adherence. While feeling limited, wanting to decide for themselves, the timing of the intervention, unmet expectations, and loss of motivation were described as barriers for adherence (Study II). A greater reduction of lactose was associated with decreased intake of calcium at the end of the radiotherapy period. A more modified fibre intake during the radiotherapy period was associated with increased vitamin C, but decreased selenium intake (Study III).Conclusions The effects from the nutrition intervention were small and inconclusive and do not support routine dietary advice aiming to modify fibre and lactose intakes as a mean to substantially reduce adverse effects from pelvic radiotherapy. Tailored nutritional interventions based on individual preferences, prior knowledge, and context, could enhance adherence. There were few associations between modified fibre and lactose intakes and nutrient intakes, thus, no recommendations can be made on whether such dietary advice should continue to be provided to men with prostate cancer undergoing pelvic radiotherapy.
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