Bakrania Anita K, Variya Bhavesh C, Patel Snehal S
Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India.
Zydus Research Centre, Ahmedabad, India.
Front Pharmacol. 2017 Dec 19;8:930. doi: 10.3389/fphar.2017.00930. eCollection 2017.
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. DEAE-Dextran has found to possess cytotoxic activity demonstrated during the various 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 and . 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.
作为乳腺癌的一种新型靶点，干扰素诱导剂已成为抗血管生成剂，其中二乙氨基乙基葡聚糖（DEAE-葡聚糖）作为一种转染剂已被使用了几个世纪。我们在此的研究结果通过深入的机制研究，解释了DEAE-葡聚糖作为三阴性乳腺癌（TNBC）抗肿瘤药物，作为抗血管生成分子出现的原因。在各种细胞毒性试验中已证明DEAE-葡聚糖具有细胞毒性活性；此外，作为一种抗氧化剂，DEAE-葡聚糖已显示出优异的活性氧清除活性。已定性和定量地测定了DEAE-葡聚糖的干扰素诱导能力，特别显示出β-干扰素的过表达。作为抗增殖活性的一种衡量指标，DEAE-葡聚糖使ki67、p53和增殖细胞核抗原（PCNA）水平降低。此外，在DEAE-葡聚糖处理的动物中，CK5/6和p63的过表达表明乳腺细胞形态得到改善，同时由于β-连环蛋白和E-钙黏蛋白的上调，细胞间黏附也得到改善。DEAE-葡聚糖的抗血管生成特性通过CD31、血管内皮生长因子（VEGF）和NOTCH1的下调得到证实。此外，最初通过Bcl2下调确定的DEAE-葡聚糖诱导的凋亡，经流式细胞术得到证实。总体而言，研究结果支持DEAE-葡聚糖作为一种新兴的抗肿瘤药物，其作用机制与β-干扰素诱导有关，可能通过抑制VEGF和NOTCH1以及诱导凋亡，但仍需进一步深入研究。
