Deguelin

Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function^[1]. Deguelin has shown promising results in targeting the hallmarks of tumor progression via inducing tumor apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis^[2][3][5].

In vitro, Deguelin was applied on head and neck squamous cell carcinoma Hep-2 cells at a various concentration (10, 25, 50, 100 and 200µM) for 72 hours or for different time points (12, 24, 48 and 72 hours) with fixed concentration (100µM). Deguelin administration caused significant cell viability loss and growth inhibition in both dose- and time- dependent manner^[3]. Deguelin (0.1 to 1.6nM) inhibited nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in primary bone marrow-derived macrophages (BMMs) for up to 7 days treatment^[4].

In vivo, Deguelin (2 or 4mg/kg), when injected intraperitoneally daily for 21 days, reduced the in vivo tumor growth of human breast cancer cell MDA-MB-231 cells transplanted subcutaneously in athymic mice^[5]. Deguelin (1 or 4mg/kg) was given by intraperitoneal injection into ovalbumin-preinduced asthmatic model mice 1h before each OVA aerosol challenge for 3 days. Deguelin effectively reduced OVA-induced inflammatory cell recruitment in BALF, decreased inflammatory cell infiltration and mucus production in lungs, suppressed airway hyperresponsiveness, and inhibited serum immunoglobulin and Th2 cytokines in asthmatic model^[6]. Deguelin (20mg/kg) were immediately injected intraperitoneally into acetaminophen (APAP) incuded acute liver failure model mice. Deguelin exerted hepatoprotective effects against APAP-induced liver injury by enhancing hepatic glutathione (GSH) levels, reducing oxidative stress markers such as malondialdehyde (MDA) and reactive oxygen species (ROS), and lowering hepatic levels of the toxic APAP metabolite NAPQI and APAP-protein adducts^[7].

References:
[1] Boyd J, Han A. Deguelin and Its Role in Chronic Diseases. Adv Exp Med Biol. 2016:929:363-375.
[2] Tuli H S, Mittal S, Loka M, et al. Deguelin targets multiple oncogenic signaling pathways to combat human malignancies. Pharmacol Res. 2021 Apr:166:105487.
[3] Yang Y L, Ji C, Bi Z G, et al. Deguelin induces both apoptosis and autophagy in cultured head and neck squamous cell carcinoma cells. PLoS One. 2013;8(1):e54736.
[4] Zhang T, Zhao K X, Han W Q, et al. Deguelin inhibits RANKL-induced osteoclastogenesis in vitro and prevents inflammation-mediated bone loss in vivo. J Cell Physiol. 2019 Mar;234(3):2719-2729.
[5] Mehta R, Katta H, Alimirah F,et al. Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells. PLoS One. 2013 Jun 10;8(6):e65113.
[6] Bao Z, Zhang P, Yao Y N, et al. Deguelin Attenuates Allergic Airway Inflammation via Inhibition of NF-κb Pathway in Mice. Int J Biol Sci. 2017 Apr 8;13(4):492-504.
[7] Gong S H, Zeng Y N, Ze Wang Z, et al. Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice. Gut Microbes. 2024 Jan-Dec;16(1):2404138.

Deguelin是四种主要天然鱼藤酮类化合物之一，从植物根部提取物中分离得到，最为人熟知的是其作为NADH:泛醌氧化还原酶（复合体I）抑制剂的作用，可导致线粒体功能的显著改变^[1]。Deguelin在靶向肿瘤进展特征方面显示出良好前景，包括诱导肿瘤细胞凋亡、细胞周期阻滞，以及抑制血管生成和转移^[2][3][5]。

在体外实验中，Deguelin以不同浓度（10、25、50、100和200µM）处理头颈部鳞状细胞癌Hep-2细胞72小时，或以固定浓度（100µM）处理不同时间点（12、24、48和72小时）。结果显示，Deguelin在剂量和时间依赖性方式下显著降低细胞活力并抑制生长^[3]。Deguelin（0.1至1.6nM）处理7天，可抑制核因子κB配体（RANKL）诱导的初级骨髓来源巨噬细胞（BMMs）来源的破骨细胞生成^[4]。

在体内实验中，Deguelin（2或4mg/kg）每日腹腔注射，连续21天，可抑制人乳腺癌MDA-MB-231细胞在裸鼠皮下移植后的肿瘤生长^[5]。Deguelin（1或4mg/kg）于每次卵清蛋白（OVA）气溶胶处理前1小时腹腔注射哮喘模型小鼠，连续3天，Deguelin有效减少OVA诱导的支气管肺泡灌洗液（BALF）中炎症细胞募集，降低肺部炎症细胞浸润和黏液分泌，抑制气道高反应性，并抑制哮喘模型中血清免疫球蛋白和Th2细胞因子的表达^[6]。在乙酰氨基酚（APAP）诱导的急性肝衰竭小鼠模型中，Deguelin（20mg/kg）于APAP处理后立即腹腔注射。Deguelin通过增强肝脏谷胱甘肽（GSH）水平、降低氧化应激标志物如丙二醛（MDA）和活性氧（ROS）水平，以及减少有毒APAP代谢物NAPQI和APAP-蛋白加合物的肝脏积累，发挥对APAP诱导肝损伤的保护作用^[7]。