蛋白激酶B
PI3K/AKT/mTOR通路
血管生成
癌症研究
下调和上调
信号转导
乳腺癌
药理学
化学
生物
癌症
医学
内科学
细胞生物学
生物化学
基因
作者
Ramesh Nivetha,Soundararajan Arvindhvv,Abdul Basit Baba,Deepak Reddy Gade,Gopal Gopisetty,K Chitrathara,K. Prathap Reddy Kallamadi,G. Bhanuprakash Reddy,Siddavaram Nagini
出处
期刊:Anti-cancer Agents in Medicinal Chemistry
[Bentham Science]
日期:2022-08-01
卷期号:22 (14): 2619-2636
被引量:6
标识
DOI:10.2174/1871520622666220204115151
摘要
The insulin/IGF-1R/PI3K/Akt signalling cascade is increasingly being linked to breast cancer development, with aldose reductase (AR) playing a key role in mediating the crosstalk between this pathway and angiogenesis. The current study was designed to investigate whether nimbolide, a neem limonoid, targets the oncogenic signaling network to prevent angiogenesis in breast cancer.Breast cancer cells (MCF-7, MDA-MB-231), EAhy926 endothelial cells, MDA-MB-231 xenografted nude mice, and tumour tissues from breast cancer patients were used for the study. The expression of AR and key players in IGF-1/PI3K/Akt signaling and angiogenesis was evaluated by qRT-PCR, immunoblotting, and immunohistochemistry. Molecular docking and simulation, overexpression, and knockdown experiments were performed to determine whether nimbolide targets AR and IGF-1R.Nimbolide inhibited AR with consequent blockade of the IGF-1/PI3K/Akt and /HIF-1alpha/VEGF signalling circuit by influencing the phosphorylation and intracellular localisation of key signaling molecules. The downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with the upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. Coadministration of nimbolide with metformin and the chemotherapeutic drugs tamoxifen/cisplatin displayed higher efficacy than single agents in inhibiting IGF-1/PI3K/Akt/AR signaling. Grade-wise increases in IGF-1R and AR expression in breast cancer tissues underscore their value as biomarkers of progression.This study provides evidence for the anticancer effects of nimbolide in cellular and mouse models of breast cancer besides providing leads for new drug combinations. It has also opened up avenues for investigating potential molecules such as AR for therapeutic targeting of cancer.
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