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Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity.
Open accessPublished version of a preprint
Abstract
The identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1alpha and HIF-1beta proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1alpha and HIF-1beta proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1alpha and HIF-1beta proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-kappaB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.
Overview
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Written from the paper’s full text.
TL;DR
Echinomycin (NSC-13502) was identified from a HIF-1-targeted compound screen as a sequence-specific DNA-binding inhibitor that blocks HIF-1 binding to hypoxia-responsive elements and reduces HIF-1-dependent transcription in U251 cells. It appears to act by binding DNA rather than by lowering HIF-1α protein, with selectivity over AP-1 and NF-κB in the assays used.
Key findings
- Of 128 active compounds from an NCI 140,000-compound HIF-1 cell-based screen, 20 inhibited HIF-1 DNA-binding activity by more than 50% at 10 µM; 12 of those also inhibited AP-1 and/or NF-κB binding, leaving 8 with relative HIF-1 selectivity.
- NSC-13502 dose-dependently inhibited recombinant HIF-1α/HIF-1β DNA binding in ELISA, with nearly complete inhibition at 320 nM, and in EMSA it did not inhibit AP-1 or NF-κB binding up to 10 µM.
- In ChIP assays, 0.5 µM NSC-13502 abolished HIF-1 binding to the VEGF promoter HRE but did not affect c-Fos binding to the cyclin D1 promoter or p65 binding to the ICAM-1 promoter; HIF-1α protein levels were not reduced.
- NSC-13502 inhibited hypoxic luciferase induction in U251-HRE cells with an EC50 of about 1.2 nM, blocked the roughly 5-fold hypoxic increase in VEGF mRNA (P < 0.01), and in microarray profiling 14 of 17 hypoxia-induced HIF-1 target genes were inhibited more than 3-fold.
Methods
- Recombinant truncated HIF-1α bHLH-PAS (amino acids 1–389) and HIF-1β bHLH-PAS (amino acids 1–475) proteins were expressed and used in a 96-well DNA-binding ELISA and EMSA with HRE, mutant HRE, AP-1, NF-κB, and E-box oligonucleotides; 128 compounds were screened at 10 µM.
- U251, U251-HRE, U251-pGL3, and MCF-7 cells were cultured under normoxia or 1% O2 hypoxia; assays included ChIP for VEGF, cyclin D1, and ICAM-1 promoters, Western blotting, luciferase reporter measurement, real-time PCR for VEGF, DNA thermal melting and ethidium bromide displacement, SRB viability, and oligonucleotide microarray analysis of about 11,000 genes.
- Main analyses compared dose-dependent inhibition, competition and supershift controls, promoter binding specificity, reporter activity, mRNA expression, and global gene-expression changes.
Limitations
- The paper states that NSC-13502’s sequence specificity may not be limited to HIF-1; it also inhibited nuclear protein binding to an E-box oligonucleotide, the binding site for Myc/Max.
- The paper states that in vivo feasibility and whether alternative dosing schedules could improve therapeutic potential remain to be established, and notes that earlier phase II clinical trials found minimal or no antitumor activity.
- Evident from the text: most mechanistic evidence comes from cell-free DNA-binding assays and cultured U251/MCF-7 cells, with no in vivo tumor efficacy experiment reported here; ChIP used 0.5 µM while the luciferase EC50 was about 1.2 nM, indicating different potency across assay contexts.
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Claims the paper makes
43 Own result · 16 No full text of the sources · 11 Own interpretation · 2 Not checked yet · 1 Supported · 1 Supported so far
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Notably, HIF-1a is overexpressed in human cancers due to hypoxia-dependent and/or hypoxia-independent pathways (6,18,19)”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Supportedcites [6] Karni R, Dor Y, Keshet E, Meyuhas O, Levitzki A. Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)-1α expression under normoxia. J Biol Chem 2002; 277: 42919–25. source
The introduction says HIF-1α is stabilized under hypoxia and that many malignant tumors have high HIF-1α levels under normoxia. The Discussion identifies enhanced HIF-1α translation as a mechanism for its strong expression in many advanced tumors under normoxia. Together, these passages support hypoxia-dependent and hypoxia-independent pathways. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [18] Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002; 64: 993–8. source
- Supportedcites [19] Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21: 3995–4004. source
The Abstract states that HIF-1α is overexpressed in primary and metastatic human tumors and that HIF-1 activity increases through both intratumoral hypoxia and genetic alterations. The Discussion further describes hypoxia and altered signaling as mechanisms that increase HIF-1α expression. (LLM, conf=0.93)
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In the paper
“We report here that echinomycin (NSC-13502) inhibits HIF-1 DNA-binding activity.”
- Also stated in: § Results · plain
“ELISA experiments (Fig. 2B) showed that NSC-13502 potently inhibited HIF-1a-389 and HIF-1h-475 DNA-binding activity in a dosedependent fashion, with almost complete inhibition at 320 nmol/L.”
- Also stated in: § Abstract · plain
“Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1A and HIF-1B proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-KB (NF-KB) consensus sequences.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Introduction
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In the paper
“In contrast, HIF-1a mRNA expression, which was slightly decreased under hypoxic conditions relative to normoxia, was not affected by NSC-13502 (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Treatment of U251 cells with NSC-13502 completely abrogated HIF-1 DNA-binding activity to the VEGF promoter.”
- Also stated in: § Abstract · plain
“Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-KB to promoter regions of corresponding target genes.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Abstract · plain
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In the paper
“More importantly, NSC-13502 up to 10 Amol/L did not inhibit DNA-binding activities induced by c-Fos and JunD to the corres-ponding AP-1 DNA-binding sequence (Fig. 2C-b)”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“In addition, cyclin D1 protein levels were not affected by treatment under hypoxia or with NSC-13502, consistent with data obtained in the ChIP assay.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Treatment of hypoxic U251 cells with NSC-13502 had a minimal effect on both constitutive and inducible HIF-1 DNA-binding activities detected in nuclear extracts (Fig. 2D-b, lane 3).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“In contrast, NSC-13502 did not significantly affect luciferase expression in the U251-pGL3 control cell line under either normoxic or hypoxic conditions (Fig. 4B).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“As shown in Fig. 4A, NSC-13502 very potently inhibited hypoxic induction of luciferase expression in U251-HRE in a dose-dependent fashion with an EC 50 of f1.2 nmol/L.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“More importantly, NSC-13502 up to 10 Amol/L did not inhibit DNA-binding activities induced by c-Fos and JunD to the corres-ponding AP-1 DNA-binding sequence (Fig. 2C-b) or the binding of p65 to the NF-nB consensus sequence (Fig. 2C-c).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“The melting temperature (T m ) of HRE DNA was increased from 51.5jC to 65jC (26.2% increase), whereas only a 5.5jC increase for NF-nB binding and a 5jC increase for AP-1-binding oligonucleotides were observed”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“As shown in Fig. 5A, hypoxia induced a 5-fold increase in VEGF mRNA expression, which was significantly (P < 0.01) inhibited by addition of NSC-13502 in a dose-dependent fashion.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As shown in Fig. 5A, hypoxia induced a 5-fold increase in VEGF mRNA expression, which was significantly (P < 0.01) inhibited by addition of NSC-13502 in a dose-dependent fashion.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, NSC-13502 did not affect the binding of AP-1 (c-Fos) to the cyclin D1 promoter or the binding of NF-nB (p65) to the ICAM-1 promoter, transcription factors that were constitutively present in untreated U251 cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Expressed recombinant HIF-1A and HIF-1B proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE).”
- Also stated in: § Results · plain
“EMSA experiments showed that HIF-1a-389 and HIF-1h-475 recombinant proteins mediated a specific DNA-binding activity to an oligonucleotide containing the canonical HIF-1-binding site (HRE), which was competed for by addition of excess unlabeled WT, but not mutant, oligonucleotide (Fig. 1B).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Abstract
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In the paper
“In contrast, addition of NSC-13502 to the binding reaction in vitro completely abrogated HIF-1-dependent DNA-binding activities detected in nuclear extracts from hypoxic U251 cells (Fig. 2D-b, lane 4).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“In conclusion, NSC-13502 does not affect HIF-1a protein levels and does not have a general effect on other proteins.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Importantly, NSC-13502 did not affect the binding of AP-1 (c-Fos) to the cyclin D1 promoter or the binding of NF-nB (p65) to the ICAM-1 promoter, transcription factors that were constitutively present in untreated U251 cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, addition of NSC-13502 to the DNA-binding reaction completely abrogated binding of nuclear proteins to the DNA (lane 4), providing further evidence of the sequence specificity of NSC-13502.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Fourteen of the 17 HIF-1-inducible genes were significantly inhibited by NSC-13502 by >3-fold (Table 1).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“EMSA results showed that all 20 compounds inhibited HIF-1 DNA-binding activity, consistent with results obtained in ELISA.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In EMSA, NSC-13502 showed a significant degree of specificity between inhibiting binding of HIF-1 to the HRE, which contains 5V-ACGT-3V in its core sequence, and unrelated sequences recognized by the AP-1 or NF-nB family of transcription factors.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
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In the paper
“As shown in Fig. 4C, 94%, 80%, and 42% of hypoxiainduced luciferase expression was restored in cells in which NSC-13502 was washed out after 4-hour treatment at 5, 10, and 20 nmol/L, respectively, indicating that the DNA-binding activity of NSC-13502 is in fact reversible.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Consistent with data from the primary high-throughput screen, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells”
- Also stated in: § Discussion · plain
“NSC-13502 inhibits hypoxic induction of luciferase expression in U251-HRE cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
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In the paper
“Moreover, 10 known HIF-1-inducible genes were identified among the 65 genes inhibited >4-fold by NSC-13502 under hypoxic conditions.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“the ability of NSC-13502 to block HIF-1 DNA binding of endogenous nuclear proteins from hypoxic treated cells, but only when the compound was added directly to the binding reaction”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
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In the paper
“Eight compounds showed a relative specificity for inhibition of HIF-1 DNA binding (Supplementary Fig. S1).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“Notably, more genes were down-regulated under hypoxic than normoxic conditions (451 versus 276 by z2-fold and 65 versus 36 by z4-fold)”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“As shown in Fig. 3B, hypoxia induced HIF-1a protein accumulation, which was slightly increased by addition of NSC-13502.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“However, 12 of 20 compounds also inhibited either AP-1 or NF-nB DNA binding or both, suggesting that these compounds were nonspecific inhibitors of protein DNA binding (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“In particular, 17 of 109 genes induced by hypoxia by >2.5-fold could be identified as HIF-1-inducible genes based on published results.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
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In the paper
“NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
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In the paper
“As shown in Fig. 3B, hypoxia induced HIF-1a protein accumulation, which was slightly increased by addition of NSC-13502.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the ability of NSC-13502 to block HIF-1 DNA binding to the HRE of VEGF promoter detected by ChIP.”
- Also stated in: § Discussion · plain
“NSC-13502 inhibits HIF-1 binding to the HRE of the VEGF promoter in cultured cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, we found that more genes were down-regulated than up-regulated”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Twenty of 128 compounds inhibited HIF-1h-389 and HIF-1h-475 DNA-binding activity by >50% relative to untreated control at the 10 Amol/L concentration (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, we found that NSC-13502 completely inhibited DNA-binding activities to an oligonucleotide containing the E-box sequence detected in nuclear extracts harvested from untreated MCF-7 cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results show that NSC-13502 inhibits DNA binding of endogenous full-length HIF-1a and HIF-1h proteins and are consistent with the possibility that NSC-13502 inhibits HIF-1 DNA binding by interacting with DNA and not by interfering with protein-protein interaction.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.”
- Also stated in: § Introduction · hedged
“Our data provide proof-of-principle that it is possible to identify small molecules that specifically inhibit HIF-1 DNA binding”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · hedged
In the paper
“echinomycin (NSC-13502), a smallmolecule known to bind DNA in a sequence-specific fashion”
- Also stated in: § Results · boosted
“NSC-13502 is a small molecule known to bind DNA in a sequence-specific fashion (15).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Abstract
What the sources say
- Not checked — no full text of the sourcecites [15] Van Dyke MM, Dervan PB. Echinomycin binding sites on DNA. Science 1984; 225: 1122–7. source
boosted- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · boosted
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that NSC-13502 exhibits a higher affinity for HRE core sequence than AP-1-or NF-nB-binding core sequences.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“consistent with the possibility that NSC-13502 inhibited preferentially HIF-1-dependent gene expression.”
- Also stated in: § Results · hedged
“In conclusion, our results show that expression of a limited number of genes is affected by treatment of U251 cells with NSC-13502 and they are consistent with a predictable pattern of inhibition of known HIF-1-inducible genes.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · hedged
In the paper
“HIF-1 induces expression of genes whose products are involved in cancer cells survival, glycolysis, angiogenesis, migration, and invasion (5).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [5] Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“However, minimal or no antitumor activity was found in phase II clinical trials.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [47] Foster BJ, Clagett-Carr K, Shoemaker DD, et al. Echinomycin: the first bifunctional intercalating agent in clinical trials. Invest New Drugs 1985; 3: 403–10. source
- Not checked — no full text of the sourcecites [48] Muss HB, Blessing JA, DuBeshter B. Echinomycin in recurrent and metastatic endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 1993; 16: 492–3. source
- Not checked — no full text of the sourcecites [49] Wadler S, Tenteromano L, Cazenave L, et al. Phase II trial of echinomycin in patients with advanced or recurrent colorectal cancer. Cancer Chemother Pharmacol 1994; 34: 266–9. source
- Not checked — no full text of the sourcecites [50] Chang AY, Kim K, Boucher H, et al. A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587). Cancer 1998; 82: 292–300. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“they are consistent with a predictable pattern of inhibition of known HIF-1-inducible genes.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is, however, conceivable that the sequence specificity of NSC-13502 may not be restricted to HIF-1 but may include other transcription factors that have similar core-binding sites in their DNA consensus sequences.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“overexpression of HIF-1a has been implicated as a poor prognostic indicator in a variety of tumors (20)(21)(22)(23).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not matchedcites [20] Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999; 59: 5830–5.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [21] Shibaji T, Nagao M, Ikeda N, et al. Prognostic significance of HIF-1α overexpression in human pancreatic cancer. Anticancer Res 2003; 23: 4721–7.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [22] Bachtiary B, Schindl M, Potter R, et al. Overexpression of hypoxia-inducible factor 1α indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res 2003; 9: 2234–40.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“NSC-13502, at 1.2 to 1.5 mg/m 2 once weekly for 4 weeks or once every 3 to 4 weeks (47-50), has been extensively tested in phase I-II clinical trials.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [47] Foster BJ, Clagett-Carr K, Shoemaker DD, et al. Echinomycin: the first bifunctional intercalating agent in clinical trials. Invest New Drugs 1985; 3: 403–10. source
- Not checked — no full text of the sourcecites [48] Muss HB, Blessing JA, DuBeshter B. Echinomycin in recurrent and metastatic endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 1993; 16: 492–3. source
- Not checked — no full text of the sourcecites [49] Wadler S, Tenteromano L, Cazenave L, et al. Phase II trial of echinomycin in patients with advanced or recurrent colorectal cancer. Cancer Chemother Pharmacol 1994; 34: 266–9. source
- Not checked — no full text of the sourcecites [50] Chang AY, Kim K, Boucher H, et al. A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587). Cancer 1998; 82: 292–300. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fewer genes were changed by z4-fold, suggesting that NSC-13502 has a limited effect on global gene expression (Fig. 5B).”
- Also stated in: § Discussion · plain
“Global analysis of gene expression using oligonucleotide arrays containing sequences representing f11,000 human genes showed that a relatively small number of genes are changed by addition of NSC-13502 under either normoxic or hypoxic conditions.”
- Also stated in: § Results · plain
“In conclusion, our results show that expression of a limited number of genes is affected by treatment of U251 cells with NSC-13502”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · plain
In the paper
“NSC-13502, a cyclic peptide of the family of quinoxaline antibiotics that was originally isolated from Streptomyces echinatus (45), is a small molecule known to bind DNA in a sequence-specific fashion.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [15] Van Dyke MM, Dervan PB. Echinomycin binding sites on DNA. Science 1984; 225: 1122–7. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We provide here proof-of-principle that NSC-13502 can in fact inhibit, in a sequence-specific fashion, the binding of HIF-1 to its cognate DNA-binding sequence.”
- Also stated in: § Discussion · boosted
“We believe that these results provide strong evidence that NSC-13502 interferes with HIF-1 DNA binding in a sequencespecific fashion.”
- Also stated in: § Discussion · plain
“NSC-13502 specifically inhibits HIF-1 DNA binding to the HRE.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · boosted
In the paper
“However, most of the activities of transcription factors are mediated by protein-protein interaction or binding to DNA in a sequence-specific fashion, both of which are conventionally considered challenging targets for development of small-molecule inhibitors (2).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Introduction
What the sources say
- Not checked — no full text of the sourcecites [2] Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 2004; 3: 301–17. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 9
- It may state two separate claims as one. 17
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, a synthetic pyrroleimidazole polyamide that inhibits in a sequence-specific fashion HIF binding to the HRE of the VEGF promoter (44) caused 264 and 73 genes to be down-regulated and up-regulated by 2-fold, respectively, at a concentration of 1 Amol/L.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Supportedcites [44] Olenyuk BZ, Zhang GJ, Klco JM, et al. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A 2004; 101: 16768–73. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NSC-13502 caused f50% displacement of ethidium bromide on HRE oligonucleotide at 3 Amol/L, whereas no significant influence on AP-1 oligonucleotide was observed even at a concentration of 10 Amol/L (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results clearly show that NSC-13502 specifically inhibits HIF-1, but not AP-1 or NF-nB, binding activity to endogenous promoters in cultured cells.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“451 versus 276 by z2-fold and 65 versus 36 by z4-fold”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More importantly, NSC-13502 under the same experimental conditions did not block the binding of c-Fos to the AP-1 site of the cyclin D1 promoter or the binding of p65 to the NF-nB site of the ICAM-1 promoter.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“only 186 genes were up-regulated under normoxia and 197 under hypoxia.”
- Also stated in: § Discussion · plain
“addition of NSC-13502 to U251 cells cultured under normoxic conditions only down-regulated or up-regulated 276 and 186 genes, respectively, by z2-fold.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Figure 2A shows the chemical structure of NSC-13502, one of the most potent compounds identified in the HIF-1 cell-based high-throughput screen and further validated using DNA-binding assays.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, HIF-1a mRNA expression, which was slightly decreased under hypoxic conditions relative to normoxia, was not affected by NSC-13502 (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“276 and 451 genes were down-regulated by z2-fold under normoxic or hypoxic conditions, respectively, in the presence of NSC-13502 (Fig. 5B).”
- Also stated in: § Discussion · plain
“addition of NSC-13502 to U251 cells cultured under normoxic conditions only down-regulated or up-regulated 276 and 186 genes, respectively, by z2-fold.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Discussion · plain
In the paper
“HIF-1a and HIF-1h belong to the basic-helix-loop-helix (bHLH)-PAS family of transcription factors.The basic domain is responsible for sequence-specific DNA binding, whereas the HLH and the PAS domains mediate dimerization and stabilization of the complex on the DNA (12).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Introduction
What the sources say
- Not checked — no full text of the sourcecites [12] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 1996; 271: 17771–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“HIF-1 activates the transcription of genes whose products are involved in crucial aspects of cancer biology, including cell survival, glycolysis, angiogenesis, migration, and invasion (5).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Introduction
What the sources say
- Not checked — no full text of the sourcecites [5] Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Results shown thus far indicate that NSC-13502 inhibits HIF-1, but not AP-1 or NF-nB, DNA-binding activity in vitro by binding DNA in a sequence-specific fashion.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Interestingly, NSC-13502 was originally discovered as a sequence-specific DNA-binding agent (15), whose sequence specificity encompasses the core sequence (5V-CGTG-3V) of HRE consensus sequence 5V-R(A/ G)CGTG-3V (12).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
What the sources say
- Not checked — no full text of the sourcecites [15] Van Dyke MM, Dervan PB. Echinomycin binding sites on DNA. Science 1984; 225: 1122–7. source
- Not checked — no full text of the sourcecites [12] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 1996; 271: 17771–8. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Hypoxia-inducible factor-1 (HIF-1), a heterodimer composed of two subunits, HIF-1a and HIF-1h (also known as aryl hydrocarbon receptor nuclear translocator), mediates the transcriptional program to oxygen deprivation (3).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Introduction
What the sources say
- Not checked — no full text of the sourcecites [3] Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001; 7: 345–50. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“More importantly, we have shown that topotecan administered on a chronic schedule inhibits HIF-1a protein accumulation, angiogenesis, and tumor growth in U251-HRE human glioblastoma xenografts (38).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [38] Rapisarda A, Zalek J, Hollingshead M, et al. Schedule-dependent inhibition of hypoxia-inducible factor-1α protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 2004; 64: 6845–8. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The strong binding sites for NSC-13502 contain the central 2-bp sequence 5V-CG-3V, and the key recognition elements for NSC-13502 are contained in the sequences 5V-ACGT-3V and 5V-TCGT-3V (15).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [15] Van Dyke MM, Dervan PB. Echinomycin binding sites on DNA. Science 1984; 225: 1122–7. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One example is the Myc/ Max family of transcription factors, whose DNA-binding site (E-box, 5V-CACGTG-3V; ref. 46) encompasses the core sequence 5V-CGTG-3V, which is also present in the HIF-1 consensus sequence and is part of the sequence specificity of NSC-13502.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [46] Nair SK, Burley SK. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 2003; 112: 193–205. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“NSC-13502 was brought into clinical trials by the NCI 20 years ago based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma and the P388 leukemia (47).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [47] Foster BJ, Clagett-Carr K, Shoemaker DD, et al. Echinomycin: the first bifunctional intercalating agent in clinical trials. Invest New Drugs 1985; 3: 403–10. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Our group has recently shown that topotecan, a topoisomerase I poison, inhibits HIF-1a protein accumulation independently of DNA replication-mediated DNA damage, suggesting a distinct mechanism of action from the cytotoxic effects (35).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [35] Rapisarda A, Uranchimeg B, Sordet O, et al. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 2004; 64: 1475–82. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“consistent with the notion that NSC-13502 binds DNA and not HIF-1a and/or HIF-1h proteins”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of the agents described above affect targets that are also involved in other biological functions, which will ultimately determine their therapeutic activity, and they can be defined nonselective inhibitors of HIF-1.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“HIF-1a is the downstream mediator of hypoxic and nonhypoxic signaling pathways, which play a crucial role in cancer progression.”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Discussion
What the sources say
- Not checked — no full text of the sourcecites [5] Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–32. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
NSC-13502 inhibits HIF-1 DNA-binding activity in vitro by binding DNA in a sequence-specific fashion.
“Results shown thus far indicate that NSC-13502 inhibits HIF-1, but not AP-1 or NF-nB, DNA-binding activity in vitro by binding DNA in a sequence-specific fashion.If this assumption were correct, a ChIP assay would show whether NSC-13502 inhibited endogenous HIF-1 DNA-binding activity in cultured cells.”
The paper relies on this without support.
The core sequence of the HRE (5'-CGTG-3') is also present in the E-box (5'-CACGTG-3'), the DNA-binding site of the Myc/Max complex.
“The core sequence of the HRE (5V -CGTG-3V) is also present in the E-box (5V-CACGTG-3V), which is the DNA-binding site of the Myc/Max complex, raising the possibility that NSC-13502 might also inhibit the binding of nuclear proteins to the E-box.”
The paper relies on this without support.
The HRE recognized by HIF-1 contains the core sequence 5'-R(A/G)CGTG-3' and is present in promoters of HIF-1 target genes.
“The DNA-binding site recognized by HIF-1, known as hypoxia-responsive element (HRE), contains the core sequence 5V -R(A/G)CGTG-3V , which is present in promoters of HIF-1 target genes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Echinomycin preferentially intercalates into DNA at sites containing the central 5′-CG-3′ dinucleotide, a critical recognition element within the HIF consensus HRE sequence (5′-ACGT-3′), thereby preventing binding of both HIF-1α and HIF-2α to their cognate response elements [383,384].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [383]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As a result, despite its potent ability to block HIF–DNA interactions, echinomycin exhibits limited specificity and a high propensity for off-target transcriptional effects.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [383]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Echinomycin also binds DNA motifs recognized by other transcription factors, such as AP-1, NF-κB, or members of the Myc/Max family, whose E-box binding site (5′-CACGTG-3′) overlaps substantially with the HIF HRE core [383,385].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [383]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Echinomycin is a potent small-molecule inhibitor of HIF-1α, which functions through sequence-specific binding to HRE to competitively inhibit HIF-1α binding to its target genes9.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [9]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It binds specifically to the core of the HIF-1 recognition sequence 5′–CGTG-3′ in a sequence-dependent fashion precluding HIF-1 and DNA binding.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [49]
In the citing paper
“The use of echinomycin, an inhibitor that has been characterized to inhibit HIF activity without modulating HIF-α subunit protein levels (23), led also to partial restoration of insulin-induced tyrosine phosphorylation of the insulin receptor in hypoxia (data not shown).”
From Hypoxia decreases insulin signaling pathways in adipocytes. (2009) · cites this paper as [23]
In the citing paper
“the HIF complex-induced binding to HRE regions in promoters of various genes can be achieved by echinomycin [87].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [87]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
“Twenty of 128 compounds inhibited HIF-1h-389 and HIF-1h-475 DNA-binding activity by >50% relative to untreated control at the 10 Amol/L concentration (data not shown).”
§ Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity > Results
“we expressed recombinant HIF-1a-bHLH-PAS-His (HIF-1a-389) and Flag-HIF-1h-bHLH-PAS (HIF-1h-475) proteins”
Citations
Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Monks, A. P., Scudiero, D. A., Skehan, P., Shoemaker, R. H., Paull, K. D., Vistica, D. T., Hose, C. D., Langley, J. W., Cronise, P., Vaigro-Wolff, A., et al. (1991) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/83.11.757 · Cited by 3,305
Self-citation(1999) · PubMed · Cited by 2,204
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705
(2000) · PubMed · Cited by 1,445
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · cited 1×
“Notably, HIF-1a is overexpressed in human cancers due to hypoxia-dependent and/or hypoxia-independent pathways (6, 18, 19), and overexpression of HIF-1a has been implicated as a poor prognostic indicator in a variety of tumors (20–23).”
BackgroundTranscription factors as targets for cancer therapy
Darnell, J. E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc906 · Cited by 1,194
Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186
Cited by
Sorted by citations
Tumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337
HIF-1α pathway: role, regulation and intervention for cancer therapy
Masoud, G. N., & Li, W. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.007 · Cited by 1,871
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712
“intercalating drugs, including echinomycin (Kong et al., 2005) and anthracyclines, such as doxorubicin (Adriamycin) and daunorubicin (Lee et al.”
Hypoxia signalling in cancer and approaches to enforce tumour regression
Pouysségur, J., Dayan, F., & Mazure, N. M. (2006) · Nature · doi:10.1038/nature04871 · Cited by 1,676
Hypoxia-Induced Angiogenesis: Good and Evil
Krock, B. L., Skuli, N., & Simon, M. C. (2011) · Genes & Cancer · doi:10.1177/1947601911423654 · Cited by 1,236
Metadata
- Authors
- Kong, D., Park, E. J., Stephen, A. G., Calvani, M., Cardellina, J. H., Monks, A., Fisher, R. J., Shoemaker, R. H., & Melillo, G.
- Affiliations
- Science Applications International Corporation (United States) (US)
- National Cancer Institute (US)
- Venue
- Cancer Research
- Published
- 2005-10-01
- Volume
- 65
- Issue
- 19
- Pages
- 9047-9055
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2144670533
- Cited by
- 508
- References
- 53
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 23 · 2023: 25 · 2022: 31 · 2021: 34 · 2020: 26 · 2019: 22 · 2018: 23 · 2017: 26 · 2016: 22 · 2015: 23 · 2014: 20 · 2013: 23 · 2012: 26
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (n01co12400-79-0-22, N01-CO-12400)
- National Cancer Institute (N01CO12400)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- echinomycin, HIF-1, hypoxia response element, transcription factor-DNA binding, small molecule inhibitors, VEGF promoter, angiogenesis, tumor progression, metastasis, high-throughput screening
- MeSH terms
- Antibiotics, Antineoplastic, Breast Neoplasms, DNA, Neoplasm, Echinomycin, Enzyme-Linked Immunosorbent Assay, Glioma, Humans, Luciferases, Promoter Regions, Genetic, Recombinant Proteins, RNA, Messenger, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Hypoxia-Inducible Factor 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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