1*, Bhavesh C. Variya 1,2 and 1* • 1Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India • 2Zydus Research Centre, Ahmedabad, India As a novel target for breast cancer, interferon inducers have found its role as anti-angiogenic agents with diethylaminoethyl dextran (DEAE-Dextran) being a molecule used for centuries as a transfection agent. Our results herein offer an explanation for the emergence of DEAE-Dextran as an anti-tumor agent for TNBC with in-depth mechanistic approach as an anti-angiogenic molecule.
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DEAE-Dextran has found to possess cytotoxic activity demonstrated during the various in vitro cytotoxicity assays; moreover, as an anti-oxidant, DEAE-Dextran has shown to possess excellent reactive oxygen species scavenging activity. The interferon inducing capacity of DEAE-Dextran was determined qualitatively as well as quantitatively specifically demonstrating overexpression of β-interferon. As a measure of anti-proliferative activity, DEAE-Dextran exhibited reduced ki67, p53, and PCNA levels. Also, overexpression of CK5/6 and p63 in DEAE-Dextran treated animals indicated improvement in breast cell morphology along with an improvement in cell–cell adhesion by virtue of upregulation of β-catenin and E-cadherin. Anti-angiogenic property of DEAE-Dextran was concluded by the downregulation of CD31, VEGF, and NOTCH1 both in vivo and in vitro.
Further, apoptosis due to DEAE-Dextran, initially determined by downregulation of Bcl2, was confirmed with flow cytometry. Overall, results are defensive of DEAE-Dextran as an emerging anti-tumor agent with mechanisms pertaining to β-interferon induction with probable VEGF and NOTCH1 inhibition as well as apoptosis which still needs to be studied in further depth. Introduction Breast cancer is a leading cause of cancer-related mortality in females globally. This malignancy represents a heterogeneous group of tumors with characteristic molecular features and diverse response to therapy (; ).
Advances in breast cancer therapy, targets angiogenesis as a novel means of therapeutic approach for the disease especially in triple negative breast cancer where no specific targeted therapy is available till date (). Angiogenesis has a major role in tumor growth, progression, and metastasis. This is as a circumstance of high demands of oxygen within the core, creating hypoxic conditions that further lead to the production of angiogenic factors for proliferation forming tubular vessels and sprouting, leading to a deeper circulatory network in the tumor (; ). As a new target for breast cancer, interferon inducers have found its role as anti-angiogenic agents.
Till date, β-interferon has been approved for multiple sclerosis for the past two decades; however, β-interferon has also been recently studied in carcinoma cell lines and found to possess protective effect against tumor cells greater than α-interferon (). Diethylaminoethyl dextran, a polycationic derivative of dextran offers a wide range of chemical and biological properties such as; adjuvant in vaccines, agent for transfection, agent for gene therapy, stabilizer for proteins, flocculent, and agent for drug delivery.
DEAE-Dextran has also been reported to enhance production of interferons induced by polyinosinic–polycytidylic acid by various mechanisms; (1) it exerts a substantial protection of the inducer against extracellular RNase and, (2) it exerts a cell-mediated effect related to increased permeability for larger inducer molecules (,; ). Hence, we have carried out various in vitro and in vivo studies in order to determine the interferon inducing capacity of DEAE-Dextran, as well as the in-depth mechanistic approach of DEAE-Dextran as a novel and emerging anti-cancer agent for TNBC.
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