Quinacrine inhibits HIF-1α/VEGF-A mediated angiogenesis by disrupting the interaction between cMET and ABCG2 in patient-derived breast cancer stem cells

被引：20

作者：

Das, Biswajit ^{[1
]}

Dash, Somya Ranjan ^{[1
]}

Patel, Harun ^{[2
]}

Sinha, Saptarshi ^{[1
]}

Bhal, Subhasmita ^{[1
]}

Paul, Subarno ^{[1
]}

Das, Chinmay ^{[1
]}

Pradhan, Rajalaxmi ^{[1
]}

Ahmed, Iqrar ^{[2
]}

Goutam, Kunal ^{[3
]}

Kundu, Chanakya Nath ^{[1
]}

机构：

[1] Deemed Univ, Kalinga Inst Ind Technol KIIT, Sch Biotechnol, Canc Biol Div, Campus 11, Bhubaneswar 751024, Odisha, India

[2] RC Patel Inst Pharmaceut Educ & Res, Dept Pharmaceut Chem, Shirpur 425405, Dhule, India

[3] Acharya Harihar Reg Canc Ctr, Dept Surg Oncol, Cuttack 753007, Odisha, India

来源：

PHYTOMEDICINE | 2023年 / 117卷

关键词：

Patient-derived-breast-cancer-stem-cells; cMET; ABCG2; VEGF-A; Angiogenesis; Quinacrine; MARKER; TARGET; VEGF; MET;

D O I：

10.1016/j.phymed.2023.154914

中图分类号：

Q94 [植物学];

学科分类号：

071001 ;

摘要：

Background: Breast cancer stem cells (BCSCs) have a critical role in progression of breast cancer by inducing angiogenesis. Several therapeutic strategies have been designed for the treatment of breast cancer by specifically preventing angiogenesis. But there is a dearth of study regarding the treatment procedure which can specifically target and kill the BCSCs and cause lesser harm to healthy cells of the body. A plant-based bioactive compound Quinacrine (QC) specifically kills cancer stem cells (CSCs) without harming healthy cells and also inhibits cancer angiogenesis but the detailed mechanistic study of its anti-CSCs and anti-angiogenic activity is yet to explore. Hypothesis: Earlier report showed that both cMET and ABCG2 play an essential role in cancer angiogenesis. Both are present on the cell surface of CSCs and share an identical ATP-binding domain. Interestingly, QC a plant based and bioactive compound which was found to inhibit the function of CSCs marker cMET and ABCG2. These relevant evidence led us to hypothesize that cMET and ABCG2 may interact with each other and induce the production of angiogenic factors, resulting in activation of cancer angiogenesis and QC might disrupt the interaction between them to stop this phenomena. Methods: Co-immunoprecipitation assay, immunofluorescence assay, and western blotting were performed by using ex vivo patient-derived breast cancer-stem-cells (PDBCSCs) and human umbilical vein endothelial cells (HUVECs). In silico study was carried out to check the interaction between cMET and ABCG2 in presence or absence of QC. Tube formation assay using HUVECs and in ovo Chorioallantoic membrane (CAM) assay using chick fertilized eggs were performed to monitor angiogenesis. In vivo patient-derived xenograft (PDX) mice model was used to validate in silico and ex vivo results. Results: Data revealed that in a hypoxic tumor microenvironment (TME), cMET and ABCG2 interact with each other and upregulate HIF-1 alpha/VEGF-A axis to induce breast cancer angiogenesis. In silico and ex vivo study showed that QC disrupted the interaction between cMET and ABCG2 to inhibit the angiogenic response in endothelial cells by reducing the secretion of VEGF-A from PDBCSCs within the TME. Knockdown of cMET, ABCG2 or both, significantly downregulated the expression of HIF-1 alpha and reduced the secretion of pro-angiogenic factor VEGF-A in the TME of PDBCSCs. Additionally, when PDBCSCs were treated with QC, similar experimental results were obtained. Conclusion: In silico, in ovo, ex vivo and in vivo data confirmed that QC inhibited the HIF-1 alpha/VEGF-A mediated angiogenesis in breast cancer by disrupting the interaction between cMET and ABCG2.

引用

页数：14

共 39 条

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