Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Gullbo, Joachim; Fryknäs, Mårten; Rickardson, Linda; D’Arcy, Pádraig; Hägg, Maria; Wickström, Malin; Hassan, Sadia; Westman, Gunnar; Brnjic, Slavica; Nygren, Peter; Linder, Stig; Larsson, Rolf

doi:10.1016/j.bcp.2011.04.003

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…Among 4 431 a priori defined gene sets, the gene set “Chuang oxidative stress response up” exhibited the highest enrichment score for VLX60 (Figure 5A). Furthermore, in accordance with earlier published results [5], the GSEA showed that genes associated with HIF1 signaling were induced by exposure to VLX50, as opposed to VLX60 (Figure 5C–5D). This hypoxia response associated with VLX50 treatment has been shown to be consistent with iron chelation as mechanism of action [5].…”

Section: Resultssupporting

confidence: 92%

“…Furthermore, in accordance with earlier published results [5], the GSEA showed that genes associated with HIF1 signaling were induced by exposure to VLX50, as opposed to VLX60 (Figure 5C–5D). This hypoxia response associated with VLX50 treatment has been shown to be consistent with iron chelation as mechanism of action [5]. Hallmark genes associated with apoptosis were enriched in cells exposed to either drug (Figure 5F–5G).…”

Section: Resultssupporting

confidence: 92%

“…We recently reported on the identification of the thiosemicarbazone 3-(3-methoxypropyl)-1-[[(pyridin-2-yl)methylidene]amino]thiourea (CD 02750, subsequently denoted VLX50) (Figure 1A) as a hit in a phenotype-based drug screen and found it to be active against ovarian carcinoma cells both in vitro and in vivo [5]. Confirmed by a series of experiments this drug was shown to deplete intracellular iron, leading to hypoxia signaling.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

et al. 2017

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BackgroundThe thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.Materials and MethodsThe cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.ResultsVLX60 showed ≥ 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.ConclusionsThe cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

et al. 2017

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“…VLX600 was more potent than other iron chelators (i.e. Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone)8, CPX, VLX5019, and deferoxamine) (Fig. 3A–G).…”

Section: Resultsmentioning

confidence: 97%

Iron chelators target both proliferating and quiescent cancer cells

Fryknäs

Zhang

Bremberg

et al. 2016

Sci Rep

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Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

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“…To measure confluence, phase contrast images were collected over time, taking updates every 2 to 3 h, and confluence was measured, as described previously. 8,9 Data Analysis Data were exported from the IncuCyte software into Microsoft Excel. All data were then imported into GraphPad Prism software (La Jolla, CA) for graphing and statistical analysis.…”

Section: Measuring Cell Confluencementioning

confidence: 99%

Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

et al. 2013

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Angiogenesis, the formation of new vessels from preexisting vessels, involves multiple cell types acting in concert to cause endothelial cell proliferation, migration, and differentiation into microvascular arrays. Under pathologic conditions, microenvironment changes result in altered blood vessel production. Historically, in vitro angiogenesis assays study individual aspects of the process and tend to be variable, difficult to quantify, and limited in clinical relevance. Here, we describe a kinetic, quantitative, co-culture angiogenesis model and demonstrate its relevance to in vivo pharmacology. Similar to in vivo angiogenesis, a co-culture of human umbilical vein endothelial cells with normal human dermal fibroblasts remains sensitive to multiple cytokines, resulting in a concentration-dependent stimulation of tube formation over time. Treatment with axitinib, a selective vascular endothelial growth factor (VEGF) antagonist, inhibited VEGF-mediated tube length and branch point formation and was selective for inhibiting VEGF over basic fibroblast growth factor (bFGF), similar to previous studies. Conversely, an FGFR-1 selective compound, PD-161570, was more potent at inhibiting bFGF-mediated angiogenesis. These results demonstrate the cytokine dynamics, selective pharmacology, and translational application of this model system. Finally, combining quantitative angiogenic biology with kinetic, live-content imaging highlights the importance of using validated in vitro models in drug discovery research.

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Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Cited by 14 publications

References 40 publications

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

Iron chelators target both proliferating and quiescent cancer cells

Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

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