This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.
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Overexpression of caveolin‐1 in inflammatory breast cancer cells enables IBC‐specific gene delivery and prodrug conversion using histone‐targeted polyplexes
Gene therapy platforms offer a variety of potentially effective solutions for development of targeted agents that can be exploited for cancer treatment. The physicochemical properties of nanocarriers can be tuned to enhance their localization in tumors, and cell specificity can also be increased by appropriate selection of gene targets. A relatively underexploited approach to enhance therapeutic selectivity in cancer tissues is the use of nanocarriers whose nuclear targeting and uptake are triggered by the altered expression of specific endomembrane trafficking proteins in cancer cells. Previously, we showed that histone 3 (H3) peptide‐targeted DNA polyplexes traffic to the nucleus efficiently through caveolar endocytosis followed by transfer through the Golgi and endoplasmic reticulum (ER). We hypothesized that these polyplexes would exhibit enhanced activity in inflammatory breast cancer (IBC) cells, which overexpress caveolin‐1 as part of their invasive phenotype, and we also posited that this targeting effect could be exploited to facilitate IBC‐specific transfection and prodrug conversion in the presence of normal breast epithelial cells. Using cellular transfection experiments, function‐blocking assays, and confocal imaging in both IBC SUM149 cell monocultures and IBC SUM149 co‐cultures with MCF10A normal breast epithelial cells, we found that our H3‐targeted polyplexes selectively transfected IBC SUM149 cells at a 4‐fold higher level than normal breast epithelial cells. This selectivity and increased transfection were caused by a 2.2‐fold overexpression of caveolin‐1 in IBC SUM149 cells, which led to increased polyplex trafficking to the nucleus through the Golgi and ER. We also saw similar enhancements in cell selectivity and transfection when cells were transfected with a suicide gene/prodrug combination, as the increased expression of the suicide gene in IBC SUM149 cells led to a 55% decrease in viability in IBC SUM149 cells as compared to a 25% decrease in MCF10A cells. These findings demonstrate that differences in the expression of the endocytic membrane protein caveolin‐1 can be exploited for cell‐selective gene delivery, and ultimately, these gene‐based targeting approaches may be useful in potential treatments for aggressive cancer types. Biotechnol. Bioeng. 2016;113: 2686–2697. © 2016 Wiley Periodicals, Inc.
- NSF-PAR ID:
- 10237045
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Biotechnology and Bioengineering
- Volume:
- 113
- Issue:
- 12
- ISSN:
- 0006-3592
- Format(s):
- Medium: X Size: p. 2686-2697
- Size(s):
- ["p. 2686-2697"]
- Sponsoring Org:
- National Science Foundation
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