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Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer
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-depende...
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Published in: | Nanomedicine 2020-10, Vol.29, p.102278-102278, Article 102278 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
In solid tumors with HIF-1α overexpression, the in vivo efficacy of HIF-1α inhibitor echinomycin is formulation-dependent. Formulated in Cremophor, echinomycin performed poorly in clinical trials of solid tumors and, here, is shown to be similarly toxic and ineffective in mouse models of solid tumors. In contrast, reformulation of echinomycin in nanoliposomes widened therapeutic index, more potently inhibited HIF-1α transcription in tumor cells, and enabled direct elimination of established metastasis in vivo. Our data indicate that, with proper formulation, echinomycin may fulfill the unmet need for safe and effective therapeutic HIF inhibition in metastatic cancer. [Display omitted] |
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ISSN: | 1549-9634 1549-9642 1549-9642 |
DOI: | 10.1016/j.nano.2020.102278 |