Review ArticleLiposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer
Graphical Abstract
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.
Section snippets
Materials
All cell lines were purchased from American Type Culture Collection (Manassas, VA) except for SUM-159 (gift from Dr. Max Wicha's laboratory, University of Michigan) and TUBO (gift from Dr. Yangxin Fu's laboratory, University of Texas). All experiments were performed with mycoplasma-free cells. Anti-HIF-1α (GTX127309) was purchased from GeneTex (Irvine, CA), anti-Vimentin (NBP2-12472) from Novus Biologicals (Centennial, CO), anti-cleaved Capase 3 from Cell Signaling (Danvers, MA), and anti-Ki67
Echinomycin effectively targets HIF-1α-dependent breast cancer
Although HIF-1α is normally degraded under normoxia, non-canonical mechanisms exist to promote its stability regardless of oxygen tension in cancer cells, including breast cancer.3 We evaluated HIF-1α protein in breast cancer cell lines under normoxia, with or without the hypoxia mimetic CoCl2. Although detectable in HER2+ cell lines, HIF-1α protein was particularly higher in TNBC cell lines SUM-159 and MDA-MB-231 (Figure 1, A). HIF-1α protein levels under normoxia corresponded to the breast
Discussion
HIF-1α is overexpressed in 70% of human cancers.40 HIF-1α drives tumor progression because it orchestrates fundamental processes such as angiogenesis, glycolytic switch, and metastasis.8 It is therefore of interest to consider whether poor outcomes in previous trials were due to improper formulation, or poor choice of targets/targeting agents. The termination of echinomycin in clinical trials immediately preceded the first clinical report identifying HIF-1α as a potential target for cancer.8,10,
Acknowledgment
The formulation described herein was characterized by the Nanotechnology Characterization Laboratory as part of its free Assay Cascade characterization service for cancer nanomedicines, which is supported by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.
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Declaration of competing interest: Yang Liu and Pan Zheng are co-founders of OncoImmune, Inc., which has licensed the technology from the Children's National Medical Center. No potential conflicts of interest were disclosed by other authors.
Funding: This study was supported by the grants from the National Institutes of Health National Cancer Institute (CA171972, CA183030 (Yang Liu), CA164469 (Yin Wang)) and a grant from OncoImmune, Inc. Christopher M. Bailey received stipend support from the Institute of Biomedical Sciences at The George Washington University during part of the studies.
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These authors contributed equally to this work.