Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer
Open accessAbstract
Hypoxia-inducible factor 1α (HIF-1α) is recognized as a prime molecular target for metastatic cancer. However, no specific HIF-1α inhibitor has been approved for clinical use. Here, we demonstrated that in vivo efficacy of echinomycin in solid tumors with HIF-1α overexpression is formulation-dependent. Compared to previously-used Cremophor-formulated echinomycin, which was toxic and ineffective in clinical trials, liposomal-echinomycin provides significantly more inhibition of primary tumor growth and only liposome-formulated echinomycin can eliminate established triple-negative breast cancer (TNBC) metastases, which are the leading cause of death from breast cancer, as available therapies remain minimally effective at this stage. Pharmacodynamic analyses reveal liposomal-echinomycin more potently inhibits HIF-1α transcriptional activity in primary and metastasized TNBC cells in vivo, the latter of which are HIF-1α enriched. The data suggest that nanoliposomal-echinomycin can provide safe and effective therapeutic HIF-1α inhibition and could represent the most potent HIF-1α inhibitor in prospective trials for metastatic cancer.
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15 of 52 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
HIF-1α inhibition has shown success as a therapeutic strategy in mouse models of metastatic breast cancer.
“HIF-1α inhibition has shown success as a therapeutic strategy in mouse models of metastatic breast cancer6, 7.”
Quote in the paperSubstantial claim2 of 2 sources checked - Premisecitation
In breast cancer, HIF-1α acts as a master regulator for the expression of genes that promote tumor growth, vascularization, and metastasis.
“In breast cancer, HIF-1α acts as a master regulator for the expression of genes that promote tumor growth, vascularization, and metastasis4.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] source
- Premisecitation
HIF-1α expression in primary tumor breast cancer cells promotes metastasis.
“It is known that HIF-1α expression in primary tumor breast cancer cells promotes metastasis, although from a clinical perspective this concept has limited value since prognosis weighs heavily on the stage of progression at time of surgical resection39.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [39] source
The 'Metastatic breast cancer' and 'Models of breast cancer' sections discuss how primary breast tumors metastasize, but do not address whether HIF-1α expression promotes that process. Searches for HIF-1α and hypoxia-inducible factor found no passage making the attributed link; page numbers were unavailable in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Premisecitation
Liposomal formulation increased the systemic exposure of echinomycin in the blood circulation.
“We have recently reported that liposomal formulation increased the systemic exposure of Echinomycin in the blood circulation36.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] source
- Premisecitation
HIF-1α drives tumor progression because it orchestrates angiogenesis, glycolytic switch, and metastasis.
“HIF-1α drives tumor progression because it orchestrates fundamental processes such as angiogenesis, glycolytic switch, and metastasis8.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] source
- Findingown data
Genetic depletion of the HIF1A isoform was sufficient to abrogate tumor growth in xenogeneic recipient mice.
“Accordingly, genetic depletion of the HIF1A isoform was sufficient to abrogate tumor growth in xenogeneic recipient mice (Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
HIF-1α protein levels under normoxia corresponded to breast cancer cells' susceptibility to echinomycin after 24 or 48 hours treatment.
“HIF-1α protein levels under normoxia corresponded to the breast cancer cells’ susceptibility to echinomycin after 24 hours (Figure 1B) or 48 hours (Figure S1) treatment, suggesting oncogenic addiction.”
Quote in the paperSubstantial claim - Findingown data
HIF1A is required for TNBC growth and metastatic potential, even under normoxia.
“Indeed, our analysis using SUM-159 cells with Crispr/Cas9 knockout of HIF1A confirmed that HIF1A is required for TNBC growth and metastatic potential, even under normoxia.”
Quote in the paperSubstantial claim - Findingown data
Echinomycin reduced mRNA levels of CITED2, VEGFA, SLC2A3, and SDF1 in a dose-dependent manner in SUM-159 cells.
“mRNA levels of CITED2, VEGFA, SLC2A3, and SDF1 were reduced in a dose-dependent manner (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
DMSO-formulated echinomycin has shown little efficacy in treatment of solid tumors in mice.
“However, this formulation has shown little efficacy in treatment of solid tumors in mice (our unpublished observations).”
Quote in the paperSubstantial claim - Findingown data
Liposomal-echinomycin had a narrow polydispersity index of ~0.05 by DLS.
“Liposomal-echinomycin displayed an average hydrodynamic diameter of 98 nm and high uniformity (Figure 2A&B, Table S2), with narrow polydispersity index (PdI) of ~0.05 by DLS (Figure 2C, Table S2).”
Quote in the paperNot a substantial claim - Findingown data
HIF1A(−/−) SUM-159 cells were less sensitive to echinomycin compared to empty vector (WT).
“HIF1A(−/−) SUM-159 cells were less sensitive to echinomycin compared to empty vector (WT).”
Quote in the paperSubstantial claim - Findingown data
Knockout of HIF1A alone severely inhibited SUM-159 growth by colony forming assay.
“Knockout of HIF1A alone severely inhibited SUM-159 growth by colony forming assay (Figure S2A) and metastatic potential determined by transwell migration and wound healing assays (Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
Knockout of HIF1A alone severely inhibited SUM-159 metastatic potential determined by transwell migration and wound healing assays.
“Knockout of HIF1A alone severely inhibited SUM-159 growth by colony forming assay (Figure S2A) and metastatic potential determined by transwell migration and wound healing assays (Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
The physiochemical characteristics of liposomal-echinomycin were highly reproducible between batches.
“These physiochemical characteristics were highly reproducible between batches (Table S2).”
Quote in the paperNot a substantial claim - Findingown data
HIF-1α protein is particularly higher in TNBC cell lines SUM-159 and MDA-MB-231 under normoxia.
“Although detectable in HER2+ cell lines, HIF-1α protein was particularly higher in TNBC cell lines SUM-159 and MDA-MB-231 (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
CrEL-echinomycin at a maximally-tolerable regimen did not inhibit tumor growth in SUM-159 xenografts.
“However, no tumor growth inhibition was observed (Figure 1 F).”
Quote in the paperSubstantial claim - Findingown data
In terms of body weight loss, 0.35 mg/kg liposomal-echinomycin was equitoxic to 0.25 mg/kg CrEL-echinomycin.
“In terms of body weight loss, 0.35 mgkg−1 liposomal-echinomycin was equitoxic to 0.25 mgkg−1 of CrEL-echinomycin (Figure 3B).”
Quote in the paperSubstantial claim - Findingreasoning
All echinomycin-treated groups showed evidence of glycogen depletion in the liver.
“In the liver, all echinomycin-treated groups showed evidence of glycogen depletion, consistent with the reduction in food intake that we observed at these doses (Figure 3F, panels ii, iii).”
Quote in the paperNot a substantial claim - Findingown data
Echinomycin decreased expression of HIF target genes CITED2, VEGFA, SLC2A3, and PGK1 in primary tumor tissues of MDA-MB-231 and SUM-159 xenografts in a dose- and formulation-dependent manner.
“In a dose- and formulation-dependent manner mirroring the efficacy data, echinomycin decreased expression of HIF target genes CITED2, VEGFA, SLC2A3, and PGK1 in primary tumor tissues of MDA-MB-231 and SUM-159 xenografts (Figure 4F&G).”
Quote in the paperSubstantial claim - Findingown data
Hepatitis and steatosis were observed in recipients of CrEL-echinomycin.
“In addition, hepatitis and steatosis were observed in recipients of CrEL-echinomycin (Figure 3F, panels iv and v, respectively).”
Quote in the paperSubstantial claim - Findingown data
Mice receiving the same dose/schedule of liposomal-echinomycin were visually indistinguishable from control mice.
“While these mice experienced rapid, progressive weight loss, mice receiving the same dose/schedule of liposomal-echinomycin were visually indistinguishable from control mice (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
1 mg/kg CrEL-echinomycin was 100% lethal by day 7 post-administration.
“While 1 mgkg−1 of CrEL-echinomycin was 100% lethal by day 7 post-administration, the same dose of liposomal-echinomycin did not reach LD50 (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Liposomal-echinomycin produced particularly profound inhibition of metastasis compared to CrEL-echinomycin, significant between the two formulations even at the equivalent dose.
“However, the data revealed particularly profound inhibition of metastasis for liposomal-echinomycin compared to CrEL-echinomycin, which was significant between the two formulations, even at the equivalent dose (Figure 5A-F).”
Quote in the paperSubstantial claim - Findingown data
Hydrodynamic diameter, PdI, and zeta potential of liposomal-echinomycin remained stable for at least 18 months at 4°C.
“Hydrodynamic diameter, PdI, and zeta potential remained stable for at least 18 months (Figure 2E&F).”
Quote in the paperNot a substantial claim - Findingown data
At 0.25 mg/kg MTD, CrEL-echinomycin demonstrated slight to modest therapeutic activity against SUM-159 and MDA-MB-231 primary tumor growth.
“At 0.25 mgkg−1, its maximum-tolerated dose (MTD), CrEL-echinomycin demonstrated slight to modest therapeutic activity against SUM-159 and MDA-MB-231 primary tumor growth, respectively (Figure 4A&B), which can be attributed to the increase in dose strength compared to our preliminary studies (Figure 1F).”
Quote in the paperNot a substantial claim - Findingown data
At 0.35 mg/kg, liposomal-echinomycin apparently eradicated liver metastasis in the MDA-MB-231 model.
“At 0.35 mgkg−1, liposomal-echinomycin apparently eradicated liver metastasis in the MDA-MB-231 model (Figure 5C&D), and nearly eradicated lung metastasis in both models (Figure 5A&B, Figure 5E&F).”
Quote in the paperSubstantial claim - Findingown data
Reductions in HIF-1α levels followed the same dose- and formulation-dependent trend in tumor sections.
“Reductions in HIF-1α levels also followed the same dose- and formulation-dependent trend in the tumor sections (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
H&E staining revealed tumor necrosis corresponding to the dose and formulation of echinomycin.
“H&E staining revealed tumor necrosis corresponding to the dose and formulation of echinomycin (Figure 4C).”
Quote in the paperNot a substantial claim - Findingown data
Immunofluorescence analysis of cleaved-caspase 3 indicated that liposomal-echinomycin more potently induced apoptosis of tumor cells vs CrEL-echinomycin.
“Immunofluorescence analysis of Ki67 and cleaved-caspase 3 in the primary tumors indicated that liposomal-echinomycin more potently inhibited the proliferation of tumor cells and induced their apoptosis, respectively, vs CrEL-echinomycin (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
Lungs showed evidence of multi-focal pleuritis with mineralization, hemorrhage, and necrosis in CrEL-echinomycin recipients.
“Lungs showed evidence of multi-focal pleuritis with mineralization, hemorrhage, and necrosis (Figure 3F, panel xii).”
Quote in the paperSubstantial claim - Findingown data
The highest amount of echinomycin was found in liver, followed by kidney, spleen, lung, heart, and tumor.
“The highest amount of echinomycin was found in liver, followed by kidney, spleen, lung, heart, and tumor (Figure S4).”
Quote in the paperNot a substantial claim - Findingown data
No lesions were found in heart, adrenal gland, small intestine, pancreas, or muscle tissues for any mice.
“We found no lesions in the heart, adrenal gland, small intestine, pancreas, or muscle tissues for any mice.”
Quote in the paperSubstantial claim - Findingown data
Lung-metastatic SUM-159 cells had higher HIF-1α transcriptional activity compared to cultured primary cells.
“Compared to cultured primary cells, lung-metastatic SUM-159 cells had higher HIF-1α transcriptional activity (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
Starting at 0.25 mg/kg, there was a significant decrease in mean daily food consumption for all mice receiving echinomycin, regardless of formulation.
“Starting at 0.25 mgkg−1, there was significant decrease in mean daily food consumption for all mice receiving echinomycin, regardless of the formulation.”
Quote in the paperSubstantial claim - Findingown data
Liposomal-echinomycin kept for 3 or 18 months in storage was indistinguishable in potency from a fresh batch of liposomal-echinomycin or free echinomycin.
“Liposomal-echinomycin kept for 3 or 18 months in storage was indistinguishable in potency from of a fresh batch of liposomal-echinomycin or free echinomycin (Figure 2H).”
Quote in the paperNot a substantial claim - Findingown data
Immunofluorescence analysis of Ki67 indicated that liposomal-echinomycin more potently inhibited proliferation of tumor cells vs CrEL-echinomycin.
“Immunofluorescence analysis of Ki67 and cleaved-caspase 3 in the primary tumors indicated that liposomal-echinomycin more potently inhibited the proliferation of tumor cells and induced their apoptosis, respectively, vs CrEL-echinomycin (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
No evidence of drug content loss was observed throughout the study.
“No evidence of drug content loss was observed throughout the study (Figure 2G).”
Quote in the paperNot a substantial claim - Findingown data
At 0.35 mg/kg, liposomal-echinomycin nearly eradicated lung metastasis in both models.
“At 0.35 mgkg−1, liposomal-echinomycin apparently eradicated liver metastasis in the MDA-MB-231 model (Figure 5C&D), and nearly eradicated lung metastasis in both models (Figure 5A&B, Figure 5E&F).”
Quote in the paperSubstantial claim - Findingown data
The remainder of the histological analysis revealed lesions only in CrEL-echinomycin recipients.
“The remainder of the analysis revealed lesions only in CrEL-echinomycin recipients.”
Quote in the paperSubstantial claim - Findingown data
Mice that received 0.25 mg/kg CrEL-echinomycin or 0.35 mg/kg liposomal-echinomycin consumed significantly less throughout observation compared to mice that received empty liposomes, CrEL vehicle, liposomal-echinomycin 0.25 mg/kg, or either formulation at 0.15 mg/kg.
“Mice that received 0.25 mgkg−1 of CrEL-echinomycin, or 0.35 mgkg−1 of liposomal-echinomycin consumed significantly less throughout the observation period compared to mice that received empty liposomes, CrEL vehicle, liposomal-echinomycin 0.25 mgkg−1, or either formulation at 0.15 mgkg−1 (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
Metastasis was reduced in echinomycin recipients, regardless of dose or formulation, for both cell lines.
“In comparison, metastasis was reduced in echinomycin recipients, regardless of dose or formulation, for both cell lines.”
Quote in the paperSubstantial claim - Findingown data
The same dose of liposomal-echinomycin did not reach LD50.
“While 1 mgkg−1 of CrEL-echinomycin was 100% lethal by day 7 post-administration, the same dose of liposomal-echinomycin did not reach LD50 (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
In kidneys, lesions included massive necrosis of proximal tubular epithelium and pyelonephritis with atrophy, degeneration and dilation of tubules in CrEL-echinomycin recipients.
“In the kidneys, lesions included massive necrosis of proximal tubular epithelium (Figure 3F, panel viii) and pyelonephritis with atrophy, degeneration and dilation of the tubules (Figure 3F, panel ix).”
Quote in the paperSubstantial claim - Findingown data
Expression of HIF-1α target genes was significantly decreased in metastasized cells of liposomal-echinomycin-treated FSR mice, indicating targeted effect on HIF-1α pathway in established metastasis.
“Consistent with high HIF-1α transcriptional activity in lung-metastatic cells (Figure 6G), we found that the expression of HIF-1α target genes was significantly decreased in the metastasized cells, indicating the targeted effect of liposomal-echinomycin on the HIF-1α pathway in established metastasis (Figure 6H).”
Quote in the paperSubstantial claim - Findingown data
Echinomycin was released from liposomal-echinomycin over ~168 hours under dialysis.
“We studied the drug release profile by dialysis followed by HPLC and found that echinomycin was released over ~168 hours under this condition (Figure 2D, Figure S3).”
Quote in the paperNot a substantial claim - Findingown data
CrEL-echinomycin caused 100% mortality in repeat dosing at 0.35 mg/kg.
“CrEL-echinomycin also caused 100% mortality in repeat dosing at 0.35 mgkg−1, (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
MTD of CrEL-echinomycin provided minimal, or even no tumor growth inhibition, depending on the treatment schedule.
“Our data showed that MTD of CrEL-echinomycin provided minimal, or even no tumor growth inhibition, depending on the treatment schedule.”
Quote in the paperSubstantial claim - Findingown data
Liposomal-echinomycin achieved superior in vivo targeting, evidenced by more potent reduction in HIF-1α targets.
“Liposomal-echinomycin also achieved superior in vivo targeting, evidenced by more potent reduction in HIF-1α targets.”
Quote in the paperSubstantial claim - Interpretationown data
Even for HIF1A-dependent tumor cells that can be effectively targeted by echinomycin in vitro, the clinical formulation was largely ineffective.
“These data demonstrate that, even for HIF1A-dependent tumor cells that can be effectively targeted by echinomycin in vitro, the clinical formulation was largely ineffective.”
Quote in the paperSubstantial claim - Premisecitation
Clinical development of echinomycin was discontinued because it was not effective for patients with solid tumors refractory to all available treatments.
“However, clinical development was discontinued because echinomycin was not found to be effective for patients with solid tumors that were refractory to all available treatments.”
Quote in the paperSubstantial claim0 of 10 sources checked - Interpretationown data
Lack of clinical efficacy may be due to inadequate delivery to tumor cells in vivo.
“The data suggest that lack of clinical efficacy may be due to inadequate delivery to tumor cells in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
HIF-1α is the major target of echinomycin.
“The apparent HIF-1α-dependence provides strong genetic evidence that HIF-1α is the major target of echinomycin (Figure 1E).”
Quote in the paperSubstantial claim - Premisecitation
CrEL-echinomycin caused severe nausea and vomiting, constituting its dose-limiting toxicity.
“CrEL-echinomycin also caused severe nausea and vomiting, constituting its dose-limiting toxicity11, 12, 15-21.”
Quote in the paperSubstantial claim0 of 9 sources checked - Premisecitation
Liposomes can improve drug delivery to solid tumors.
“Since liposomes can improve drug delivery to solid tumors, we explored their potential as an enabling technology for echinomycin in solid tumors26.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] source
- Interpretationown data
The correspondence between HIF-1α protein levels and echinomycin susceptibility suggests oncogenic addiction.
“HIF-1α protein levels under normoxia corresponded to the breast cancer cells’ susceptibility to echinomycin after 24 hours (Figure 1B) or 48 hours (Figure S1) treatment, suggesting oncogenic addiction.”
Quote in the paperSubstantial claim - Premisecitation
CrEL-echinomycin caused hypersensitivity reactions in clinical trials.
“in clinical trials with CrEL-echinomycin, hypersensitivity reactions were observed12, 18, 19, 21-23”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The outcomes in early clinical trials with echinomycin were likely skewed by formulation-related issues that were unknown at the time.
“Here, through the use of HIF1A-addicted breast cancer cell lines, we provide the first evidence indicating that the outcomes in early clinical trials with echinomycin were likely skewed by formulation-related issues that were unknown at the time.”
Quote in the paperSubstantial claim - Interpretationown data
The enhanced efficacy of liposomal-echinomycin at the equivalent dose to CrEL-echinomycin suggested that liposomes improved in vivo delivery of echinomycin to tumor cells.
“The enhanced efficacy of liposomal-echinomycin at the equivalent dose to CrEL-echinomycin suggested that liposomes improved in vivo delivery of echinomycin to tumor cells.”
Quote in the paperSubstantial claim - Interpretationown data
HIF-1α has an essential role in established secondary tumors.
“These results demonstrated that echinomycin directly eliminates metastasized breast cancer cells in the lung and liver and further suggested an essential role for HIF-1α in the established secondary tumors.”
Quote in the paperSubstantial claim - Interpretationown data
The potency of liposomal-echinomycin remains stable in storage for at least 18 months.
“Therefore, the potency of echinomycin is unaltered by its entrapment into the liposomes, and the potency of liposomal-echinomycin remains stable in storage for at least 18 months.”
Quote in the paperNot a substantial claim - Interpretationown data
Liposomal-echinomycin was approximately 30% less toxic than CrEL-echinomycin in terms of body weight loss and food consumption.
“This analysis demonstrated that liposomal-echinomycin was approximately 30% less toxic than CrEL-echinomycin in terms of body weight loss and food consumption.”
Quote in the paperSubstantial claim - Interpretationown data
Dose-limiting toxicities of CrEL-echinomycin may have prevented therapeutically effective doses from being reached.
“First, dose-limiting toxicities of CrEL-echinomycin may have prevented therapeutically effective doses from being reached.”
Quote in the paperSubstantial claim - Interpretationown data
Liposomal-echinomycin is less toxic than CrEL-echinomycin.
“Thus, liposomal-echinomycin is less toxic than CrEL-echinomycin.”
Quote in the paperSubstantial claim - Interpretationown data
Echinomycin directly eliminates metastasized breast cancer cells in the lung and liver.
“These results demonstrated that echinomycin directly eliminates metastasized breast cancer cells in the lung and liver and further suggested an essential role for HIF-1α in the established secondary tumors.”
Quote in the paperSubstantial claim - Interpretationown data
Histology indicated less toxicity for liposomal-echinomycin vs CrEL-echinomycin, even at an equitoxic dose in terms of body weight loss and food consumption.
“Altogether, histology indicated less toxicity for liposomal-echinomycin vs CrEL-echinomycin, even at an “equitoxic” dose in terms of body weight loss and food consumption (i.e. liposomal-echinomycin 0.35 mgkg−1 vs. CrEL-echinomycin 0.25 mgkg−1).”
Quote in the paperSubstantial claim - Interpretationown data
The potency of echinomycin is unaltered by its entrapment into the liposomes.
“Therefore, the potency of echinomycin is unaltered by its entrapment into the liposomes, and the potency of liposomal-echinomycin remains stable in storage for at least 18 months.”
Quote in the paperNot a substantial claim - Premisecitation
Clinical studies have provided considerable safety data for echinomycin.
“Clinical studies have provided considerable safety data for echinomycin10-12, 14-18, 41-45”
Quote in the paperSubstantial claim0 of 10 sources checked - Interpretationcitation
The difference in release profiles under the two conditions can be attributed to bilayer exchange.
“The difference in release profiles under the two conditions can be attributed to bilayer exchange, which has been reported for a variety of lipophilic, poorly water soluble drugs that partition into the liposomal bilayer, as reviewed by Fahr and colleagues46.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] source
- Interpretationown data
Reformulation of echinomycin via a nanoliposomal platform enables successful targeting of HIF-1α in metastatic breast cancer.
“More importantly, it indicates that reformulation of echinomycin via a nanoliposomal platform enables successful targeting of HIF-1α in metastatic breast cancer.”
Quote in the paperSubstantial claim - Interpretationreasoning
The work provides a new therapeutic approach to improve survival in patients with metastatic breast cancer.
“Since metastasis is the leading cause of breast cancer-related mortality, our work provides a new therapeutic approach to improve survival in patients with metastatic breast cancer.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 13
- May combine two claims. 21
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNo specific HIF inhibitor has been approved for clinical use.
“However, no specific HIF inhibitor has been approved for clinical use8.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDouble-knockdown of HIF1A and HIF2A in MDA-MB-231 cells impairs primary tumor growth and lung metastasis in vivo.
“Double-knockdown of HIF1A and HIF2A in MDA-MB-231 cells was reported to impair primary tumor growth and lung metastasis in vivo6.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] source
May combine two claims.
PremisecitationHIF-1α is a master transcription factor that is highly expressed in cancer tissues, including breast cancer, and is particularly enriched in triple-negative breast cancer (TNBC).
“Hypoxia-inducible factor 1α (HIF-1α) is a master transcription factor that is highly expressed in cancer tissues, including breast cancer, and is particularly enriched in triple-negative breast cancer (TNBC)2.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] source
The Basal-like summary analysis (page unavailable) identifies hyperactivated HIF1α/ARNT regulatory hubs and high pathway activity in basal-like breast cancers, most of which are TNBC. It does not establish that HIF-1α itself is highly expressed in cancer tissues generally or measured as enriched in TNBC; its finding concerns inferred pathway activity in the basal-like subtype. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEchinomycin dissolved in DMSO is active against leukemia in mice.
“We have demonstrated that echinomycin, dissolved in dimethyl sulfoxide (DMSO) is active against leukemia in mice24, 25.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [24] source
The Results report that echinomycin was effective against relapsed AML in mice, with longer survival than in vehicle-treated mice. Our copy does not say that the echinomycin given to mice was dissolved in DMSO; the Materials and methods passage mentioning dimethylsulfoxide uses it to dissolve crystals in a cell-viability assay, not to prepare the treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [25] source
The Results section, “Therapeutic elimination of leukemia stem cells (LSC) for AML,” reports that echinomycin eliminated or substantially reduced human leukemia in mice. The Experimental Procedures describe echinomycin injections but do not identify DMSO as the solvent; a search for DMSO found no supporting passage. Thus the activity in mice is supported, but the formulation is not. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationEchinomycin is a potent small-molecule inhibitor of HIF-1α that functions through sequence-specific binding to HRE to competitively inhibit HIF-1α binding to its target genes.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] source
The Results (page unavailable) identify echinomycin as a potent inhibitor of HIF-1 DNA binding and show that it binds HRE-containing DNA with relatively high affinity. They also show reduced binding of the HIF-1α/HIF-1β complex to HREs, but describe inhibition through interaction with DNA as a possibility rather than establishing a competitive mechanism. The claim overstates that mechanism and describes the target as HIF-1α alone. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationHIF-1α is degraded under normoxia but can be stabilized by oxygen-independent mechanisms, especially in cancer cells.
“Generally, HIF-1α is degraded under normoxia, but it can be stabilized by oxygen-independent mechanisms, especially in cancer cells3.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMetastasis is the leading cause of death from breast cancer.
“Metastasis is the leading cause of death from breast cancer1, 37-39.”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [1] source
- cites [37] source
- cites [38] source
The Chemotherapy for TNBC section says fewer than 30% of women with metastatic breast cancer survive five years and that virtually all women with metastatic TNBC ultimately die of their disease. It does not establish that metastasis is the leading cause of death across all breast cancer cases. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [39] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataLiposomal-echinomycin had an average zeta potential of −30 mV.
“Capillary electrophoresis revealed an average zeta potential of −30 mV (Figure 2C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataReformulating echinomycin in liposomes reduced toxicity and provided strong therapeutic effects with effective in vivo targeting of the HIF-1α pathway.
“We report here that reformulating echinomycin in liposomes reduced toxicity and provided strong therapeutic effects with effective in vivo targeting of the HIF-1α pathway.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLiposomal-echinomycin displayed an average hydrodynamic diameter of 98 nm and high uniformity.
“Liposomal-echinomycin displayed an average hydrodynamic diameter of 98 nm and high uniformity (Figure 2A&B, Table S2), with narrow polydispersity index (PdI) of ~0.05 by DLS (Figure 2C, Table S2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOn average, ALT and AST liver enzymes were slightly higher in CrEL-echinomycin- vs liposomal-echinomycin-treated mice, although the trend was not statistically significant.
“On average, ALT and AST liver enzymes were slightly higher in CrEL-echinomycin- vs liposomal-echinomycin-treated mice, although the trend was not statistically significant (Table S4).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn FSR mice, liposomal-echinomycin-treated mice were nearly free of lung metastasis in MDA-MB-231 and SUM-159 models, and free of liver metastasis in the MDA-MB-231 model.
“H&E paired with immunofluorescence staining of human vimentin in lung and liver revealed that, as in non-FSR studies, FSR mice that received liposomal-echinomycin were nearly free of lung metastasis in MDA-MB-231 (Figure 6A&B) and SUM-159 (Figure 6E&F) models, and free of liver metastasis in the MDA-MB-231 model (Figure 6C&D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt 0.25 mg/kg, the decrease in food consumption was more pronounced in mice that received CrEL-echinomycin vs liposomal-echinomycin, and post-treatment averages were significantly different.
“However, at 0.25 mgkg−1, the decrease was more pronounced in mice that received CrEL-echinomycin vs liposomal-echinomycin, and post-treatment averages in daily food intake were also significantly different between the two groups.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLiposomal-echinomycin more potently inhibited primary tumor growth in both models at its MTD (0.35 mg/kg) and even at the equivalent dose of 0.25 mg/kg.
“Liposomal-echinomycin more potently inhibited primary tumor growth in both models at its MTD (0.35 mgkg−1), and even at the equivalent dose of 0.25 mgkg−1 (Figure 4A&B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApart from slightly decreased red blood cell counts in CrEL-echinomycin-treated mice, blood indices revealed no significant differences between formulations, and all values fell within normal ranges.
“Apart from slightly decreased red blood cell counts in CrEL-echinomycin-treated mice, the blood indices revealed no significant differences between formulations, and all values fell within the normal ranges (Table S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataH&E analysis paired with immunofluorescence staining of human vimentin revealed extensive lung metastasis in vehicle-treated SUM-159 or MDA-MB-231 recipients, and extensive liver metastasis from MDA-MB-231.
“H&E analysis paired with immunofluorescence staining of human vimentin revealed extensive lung metastasis in vehicle-treated SUM-159 (Figure 5A&B) or MDA-MB-231 (Figure 5E&F) recipients, and extensive liver metastasis from MDA-MB-231 (Figure 5C&D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe reduction in average daily food intake for CrEL-echinomycin 0.25 mg/kg was 81.4% of initial, compared to 79.5% for liposomal-echinomycin 0.35 mg/kg, and post-treatment averages were not significantly different.
“Compared to pre-treatment values, the reduction in average daily food intake for mice that received CrEL-echinomycin 0.25 mgkg−1 was 81.4% of the initial, compared to 79.5% of the initial for liposomal-echinomycin 0.35 mgkg−1, and the post-treatment averages in daily food intake were not significantly different between the two groups.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataAfter i.v. administration of Lipo-EM at 0.1 mg/kg, echinomycin reached most tissues with Tmax between 0.25-1 hour.
“After i.v. administration, echinomycin reached most tissues with Tmax between 0.25-1 hour (Table S3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTerminal half-life and mean residence time of echinomycin ranged between 3.37-13.43 hours and 4.42-10.86 hours, respectively.
“Terminal half-life (T1/2) and mean residence time (MRT) ranged between 3.37-13.43 hours and 4.42-10.86 hours, respectively, and nearly all of the drug was eliminated by 72 hours post-dosing (Figure S4, Table S3).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNearly all of the drug was eliminated by 72 hours post-dosing.
“Terminal half-life (T1/2) and mean residence time (MRT) ranged between 3.37-13.43 hours and 4.42-10.86 hours, respectively, and nearly all of the drug was eliminated by 72 hours post-dosing (Figure S4, Table S3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe effect of MTD CrEL-echinomycin on metastasis was suboptimal, and only liposomal-echinomycin could eliminate liver metastasis altogether in the MDA-MB-231 model.
“The effect of MTD CrEL-echinomycin on metastasis was suboptimal, and only liposomal-echinomycin could eliminate liver metastasis altogether in the MDA-MB-231 model.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEchinomycin remained stably associated with the liposomes in long-term storage but was released within days under dialysis conditions.
“Our results showed that echinomycin remained stably associated with the liposomes in long-term storage but was released within days under dialysis conditions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHIF-1α is overexpressed in 70% of human cancers.
“HIF-1α is overexpressed in 70% of human cancers40.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataThe efficiency with which CrEL delivers the drug to its target is suboptimal; although CrEL-echinomycin and liposomal-echinomycin are equally effective in vitro, liposomal-echinomycin is significantly more effective in vivo.
“Second, the efficiency in which CrEL delivers the drug to its target is suboptimal; although CrEL-echinomycin and liposomal-echinomycin are equally effective in vitro, liposomal-echinomycin is significantly more effective in vivo.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLiposomes delivered echinomycin to relevant cells more efficiently in vivo, and could potentially provide the same advantage in humans.
“Therefore, liposomes delivered echinomycin to relevant cells more efficiently in vivo, and could potentially provide the same advantage in humans.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll experiments were performed at least three times, producing similar results.
“All experiments have been performed at least three times, producing similar results.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenToxicological analyses were performed double-blind by a certified veterinary pathologist.
“Toxicological analyses were performed double-blind by a certified veterinary pathologist.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSample sizes were determined by power calculation or prior experience.
“Sample sizes were determined by power calculation or prior experience.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee (IACUC) of Children's Research Institute or University of Maryland School of Medicine.
“All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee (IACUC) of Children’s Research Institute or University of Maryland School of Medicine.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningLiposomal-echinomycin is safer and more effective than CrEL-echinomycin, and should be tolerated better in clinical trials.
“Therefore, liposomal-echinomycin is safer and more effective than CrEL-echinomycin, and should be tolerated better in clinical trials.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were performed with mycoplasma-free cells.
“All experiments were performed with mycoplasma-free cells.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationEchinomycin has an advantage over untested HIF-1α inhibitors because safe doses have already been established in over a dozen clinical trials.
“Echinomycin has an advantage over untested HIF-1α inhibitors because safe doses have already been established in over a dozen clinical trials.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The NSG mouse xenograft models of SUM-159 and MDA-MB-231 are predictive of human TNBC metastasis and treatment response.
“Tumor cells (0.5x106-1x106) were suspended in RPMI 1640 and injected into the 2nd mammary fat pad of 6-8 weeks-aged female NSG mice.”
The paper relies on this without support.
Human vimentin-positive nodules in mouse liver or lung tissues represent metastasized human breast cancer cells.
“Metastasis was quantified in liver or lung tissues by counting human vimentin-positive nodules/view at 10x magnification.”
The paper relies on this without support.
Full surgical resection of primary tumors leaves established metastases that can be treated and assessed.
“For full surgical resection (FSR) experiments, primary tumors were resected once 5x5mm as previously described29.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
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Cites a retracted work: 10.1038/onc.2011.365
InfoThe cited work was retracted on 2023-05-23 (notice 10.1038/s41388-023-02720-8), not before this paper was published (2020-10).
Cited work 10.1038/onc.2011.365 · retracted 2023-05-23 · notice 10.1038/s41388-023-02720-8 · this paper published 2020-10
“Zhang, 2012, HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs, Oncogene, 31, 1757, 10.1038/onc.2011.365”
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Metastasis prevention: targeting causes and roots
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Thomas, J. A., Moly, A. G. G., Xavier, H., Suboj, P., Ladha, A., Gupta, G., Singh, S. K., Palit, P., & Babykutty, S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1063051 · Cited by 17 · see citing works
Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma
Huang, X., Liu, Y., Wang, Y., Bailey, C., Zheng, P., & Liu, Y. (2021) · Cancers · doi:10.3390/cancers13040694 · Cited by 16 · see citing works
“H1944 cells were injected into right flank of immunocompromised nude mice, and liposome formulated echinomycin [35] was administered subcutaneously near tumor on day 6 and day 14 at 200 μg/kg.”
MethodSelf-citationChen, C., Chen, X., Ren, B., Guo, H., Abdel-Mageed, W. M., Liu, X., Song, F., & Zhang, L. (2021) · Journal of Industrial Microbiology & Biotechnology · doi:10.1093/jimb/kuab079 · Cited by 14 · see citing works
“Oncolmmune, a clinical-stage biopharmaceutical company, is working to develop new echinomycin formulations such as nanoliposomal echinomycin to improve its half-life and therapeutic index for treating patients with hematological malignancies, such as triple-negative breast cancer (Bailey et al., 2020).”
BackgroundEchinomycin: A Journey of Challenges
Lafi, Z., Alshaer, W., Hatmal, M. M., Zihlif, M., Asha, N., Abdelnabi, H., & Awidi, A. (2023) · Jordan Journal of Pharmaceutical Sciences · doi:10.35516/jjps.v16i3.918 · Cited by 11 · see citing works
“Metastases of triplenegative breast cancer In vitro/ in vivo Liposomal formulation Effective and less toxic than conventional formulations (74)”
Molecular targets and therapeutic strategies for triple-negative breast cancer
Bhat, Y., Thrishna, M. R., & Banerjee, S. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08868-6 · Cited by 11 · see citing works
“Targeting of HIF-1 in metastatic breast cancer is made possible by the reformulation of echinomycin using a nanoli-posomal platform [28].”
Garcia, M. R., Andrade, P. B., Lefranc, F., & Gomes, N. G. M. (2024) · Marine Drugs · doi:10.3390/md22040143 · Cited by 11 · see citing works
“The antiangiogenic effects of stellettin B ( 87 ) were confirmed in two in vivo models, with VEGF mRNA expression being decreased in zebrafish embryos and reduction in angiogenesis also being recorded in murine Matrigel Plug models [325].”
Synthesis and evaluation of biarylquinoline derivatives as novel HIF-1α inhibitors
Wu, Y., Lu, M., Lin, T.-H., Chu, P., & Chang, C. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.105681 · Cited by 7 · see citing works
Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer
Varshini, M. S., Krishnamurthy, P. T., Reddy, R. A., Wadhwani, A., & Chandrashekhar, V. M. (2024) · Current Cancer Drug Targets · doi:10.2174/0115680096280750240123054936 · Cited by 6 · see citing works
Bailey, C. M., Wei, Y., Yan, J., Huang, D. Y., Zhang, P., Qi, C., Lazarski, C. A., Su, J., Tang, F., Wong, C.-S., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101236 · Cited by 5 · see citing works
Self-citationMiscellaneous small- molecule and biological approaches to targeted cancer therapy
Avendaño, C., & Menéndez, J. C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818549-0.00016-9 · Cited by 4 · see citing works
Wang, Y., & Zhou, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1605669 · Cited by 3 · see citing works
Self-citationThe Role of Intra-Tumor Hypoxia in Cancer Cells Immune Escape Mechanism
Farhangnia, P., Delbandi, A., Aghamohamadi, N., Safdarian, A. R., & Akbarpour, M. (2022) · Springer eBooks · doi:10.1007/978-3-030-80962-1_61-1 · Cited by 3 · see citing works
Yu, X., Zhu, W., Qian, H.-C., et al. (2025) · Frontiers in Chemistry · doi:10.3389/fchem.2025.1607067 · Cited by 2 · see citing works
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
HIF-опосредованные механизмы взаимосвязи устойчивости к гипоксии и опухолевого роста
Dzhalilova, D. S., & Makarova, O. V. (2021) · Biochemistry (Moscow) · doi:10.31857/s0320972521100018 · Cited by 1 · see citing works
Introduction to Cancer Genetics and Its Symbiotic Relationship
Gautam, L., Vishwakarma, M., Kanwar, I. L., Shrivastava, P., & Vyas, S. P. (2023) · Springer eBooks · doi:10.1007/978-981-19-7550-9_1
The Role of Intra-tumor Hypoxia in Cancer Cells Immune Escape Mechanism
Farhangnia, P., Delbandi, A., Aghamohamadi, N., Safdarian, A. R., & Akbarpour, M. (2025) · Springer eBooks · doi:10.1007/978-3-032-00759-9_61 · Cited by 1 · see citing works
Myeloid HIF-1α Sustains Hypoxic Fibrotic Fronts and Drives Pulmonary FibrosisPreprint
Wei, Y., Bailey, C. M., Zhang, P., Herazo-Maya, J., Karampitsakos, Τ., Pescrille, J. D., Diaz‐Mendez, F., Lee, D., Samokhin, A. O., Liu, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.09.710578
Self-citation
- Authors
- Bailey, C. M., Liu, Y., Peng, G., Zhang, H., He, M., Sun, D., Zheng, P., Liu, Y., & Wang, Y.
- Affiliations
- University of Maryland, Baltimore (US)
- Jilin University (CN)
- University of Michigan (US)
- Corresponding author
- Liu, Yang
- Wang, Yin
- ORCID
- Venue
- Nanomedicine: Nanotechnology, Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 29
- Pages
- 102278
- ISSN
- 1549-9634 (ISSN-L)
- PMC
- PMC7508926
- OpenAlex
- W3045578426
- Cited by
- 44
- References
- 53
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 11 · 2021: 13 · 2020: 1
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nanomedicine Nanotechnology Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- echinomycin, HIF-1α inhibition, liposomal formulation, triple-negative breast cancer, metastasis, tumor hypoxia, pharmacodynamics, nanoliposomes
- MeSH terms
- Animals, Echinomycin, Female, Humans, Liposomes, Neoplasm Metastasis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Triple Negative Breast Neoplasms
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