Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
Department of Chemistry, Faculty of Science, University of Yaounde I, Yaounde, Cameroon.
J Ethnopharmacol. 2021 Mar 1;267:113632. doi: 10.1016/j.jep.2020.113632. Epub 2020 Nov 27.
Tetrapleura tetraptera is an African medicinal spice used in traditional medicine to treat several ailments including cancer.
The present study was designed to evaluate the cytotoxicity of the dichloromethane-methanol (1:1) extract of the fruits of Tetrapleura tetraptera (TTF) and its constituents: (3R, 4S)-3,4-dimethyloxetan-2-one (1), luteolin (2), stigmasterol (4), 3-O-[6'-O-undecanoyl-β--glucopyranosyl]stigmasterol (6), olean-12-en-3-β-O--glucopyranoside (7), 3-O-β--glucopyranosyl-(1 → 6)-β--glucopyranosylurs-12-en-28-oic acid (8), 3-O-β--glucopyranosyl-(1 → 3)-β--glucopyranosyl-27-hydroxyolean-12-ene-28-oic acid (9), methyl-O-β--glucopyranoside (10), β--fructofuranosyl-(2 → 1)-β--glucopyranoside (11) towards a panel of cancer cell lines including MDR phenotypes. The cellular mode of induction of apoptosis by TTF and compound 7 was further investigated.
The resazurin reduction assay (RRA) was applied to determine the cytotoxicity of the studied samples. The cell cycle (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP; JC-1) and reactive oxygen species (ROS; HDCFH-DA) were measured by flow cytometry. Column chromatography was used for the purification of TTF, whilst nuclear magnetic resonance (NMR) spectroscopic analysis was applied for structural elucidation.
The botanical, TTF and the phytochemicals, 2, 7, 8 and 9 as well as doxorubicin exerted cytotoxicity against 9 cancer cell lines including drug-sensitive and drug resistant phenotypes. TTF, compound 7 and doxorubicin were the most active samples, and displayed IC values ranging from 10.27 μg/mL (in CCRF-CEM leukemia cells) to 23.61 μg/mL (against HCT116 p53 colon adenocarcinoma cells) for TTF, from 4.76 μM (against CCRF-CEM cells) to 12.92 μM (against HepG2 hepatocarcinoma cells) for compound 7, and from 0.02 μM (against CCRF-CEM cells) to 122.96 μM (against CEM/ADR5000 cells) for doxorubicin. TTF induced apoptosis in CCRF-CEM cells through MMP alteration and increased ROS production while compound 7 induced apoptosis mediated by caspases activation, MMP alteration and increased ROS production.
Tetrapleura tetraptera and some of its constituents, mostly compound 7 are good cytotoxic natural products that should be explored in depth to develop new drugs to fight cancers.
四棱豆 Tetrapleura tetraptera 是一种非洲药用香料，用于传统医学治疗多种疾病，包括癌症。
本研究旨在评估四棱豆 Tetrapleura tetraptera（TTF）及其成分（3R，4S）-3,4-二甲氧基-2-恶唑烷酮（1）、木樨草素（2）、豆甾醇（4）、3-O-[6'-O-十一烷酰基-β--吡喃葡萄糖基]豆甾醇（6）、齐墩果酸-12-烯-3-β-O--吡喃葡萄糖苷（7）、3-O-β--吡喃葡萄糖基-（1'→6）-β--吡喃葡萄糖基-urs-12-烯-28-酸（8）、3-O-β--吡喃葡萄糖基-（1'→3）-β--吡喃葡萄糖基-27-羟基齐墩果酸-12-烯-28-酸（9）、甲基-O-β--吡喃葡萄糖苷（10）、β--果糖呋喃糖苷-（2'→1）-β--吡喃葡萄糖苷（11）对包括多药耐药表型在内的一系列癌细胞系的细胞毒性。进一步研究了 TTF 和化合物 7 通过细胞凋亡的诱导方式。
采用 Resazurin 还原测定法（RRA）测定研究样品的细胞毒性。通过流式细胞术测定细胞周期（PI 染色）、凋亡（Annexin V/PI 染色）、线粒体膜电位（MMP；JC-1）和活性氧（ROS；HDCFH-DA）。柱色谱法用于 TTF 的纯化，而核磁共振（NMR）光谱分析用于结构解析。
植物学上的 TTF 及其化学成分 2、7、8 和 9 以及阿霉素对包括敏感和耐药表型在内的 9 种癌细胞系均具有细胞毒性。TTF、化合物 7 和阿霉素是最有效的样品，其 IC 值范围从 10.27μg/mL（在 CCRF-CEM 白血病细胞中）到 23.61μg/mL（在 HCT116 p53 结肠腺癌细胞中）对于 TTF，从 4.76μM（在 CCRF-CEM 细胞中）到 12.92μM（在 HepG2 肝癌细胞中）对于化合物 7，从 0.02μM（在 CCRF-CEM 细胞中）到 122.96μM（在 CEM/ADR5000 细胞中）对于阿霉素。TTF 通过 MMP 改变和增加 ROS 产生诱导 CCRF-CEM 细胞凋亡，而化合物 7 通过 caspase 激活、MMP 改变和增加 ROS 产生诱导凋亡。
四棱豆 Tetrapleura tetraptera 及其一些成分，尤其是化合物 7，是很好的细胞毒性天然产物，应深入研究开发新的抗癌药物。
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