Institute of Experimental and Clinical Pharmacology, Toxicology, and Pharmacology of Natural Products, Ulm University, D-89081 Ulm, Germany; Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Biomed Pharmacother. 2024 Oct;179:117365. doi: 10.1016/j.biopha.2024.117365. Epub 2024 Aug 31.
Mangosteen (Garcinia mangostana) is well-known for its nutritional value and health benefits. Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Here we show that the prenylated xanthones, α-mangostin, γ-mangostin, 9-hydroxycalabaxanthone (9-HCX), and garcinone E from the mangosteen pericarp exhibit cytotoxicity against a panel of human cancer cell lines including lung adenocarcinoma (A549), cervical carcinoma (HeLa), prostatic carcinoma (DU 145), pancreatic carcinoma (MIA PaCa-2), hepatocellular carcinoma (Hep G2), bladder urothelial cancer (5637), as well as the triple-negative breast cancer cells MDA-MB-231. In line with its higher predicted bioactivity score compared to other prenylated xanthones, 9-HCX induced the strongest antiproliferative and proapoptotic effects in MDA-MB-231 breast cancer xenografts in vivo. In different in vitro models, we demonstrate that prenylated xanthones from G. mangostana target mitochondria in cancer cells by inhibition of the mitochondrial respiratory chain complex II (α-mangostin, γ-mangostin, and garcinone E) and complex III (9-HCX) as shown in isolated mitochondria. Accordingly, oxidative mitochondrial respiration (OXPHOS) was inhibited, mitochondrial proton leak increased, and adenosine triphosphate (ATP) synthesis decreased as analyzed by Seahorse assay in MDA-MB-231 cells. Hence, the prenylated xanthones increased mitochondrial superoxide levels, induced mitochondrial membrane permeabilization, and initiated caspase 3/7-mediated apoptosis in MDA-MB-231 triple-negative breast cancer cells. Thus, prenylated xanthones from Garcinia mangostana exhibit anticancer activity based on interference with the mitochondrial respiration.
山竹（藤黄科藤黄属）以其营养价值和健康益处而闻名。乳腺癌是全球女性中最常见的癌症和癌症相关死亡的主要原因。在这里，我们表明来自山竹果皮的三萜烯基呫吨酮，α-倒捻子素，γ-倒捻子素，9-羟基卡拉巴嗪（9-HCX）和 Garcinone E 对一组人类癌细胞系具有细胞毒性，包括肺腺癌（A549），宫颈癌（HeLa），前列腺癌（DU 145），胰腺癌（MIA PaCa-2），肝癌（Hep G2），膀胱癌尿路上皮癌（5637）以及三阴性乳腺癌细胞 MDA-MB-231。与其他三萜烯基呫吨酮相比，9-HCX 的预测生物活性评分更高，在体内 MDA-MB-231 乳腺癌异种移植模型中诱导了最强的抗增殖和促凋亡作用。在不同的体外模型中，我们证明来自 G. mangostana 的三萜烯基呫吨酮通过抑制线粒体呼吸链复合物 II（α-倒捻子素，γ-倒捻子素和 Garcinone E）和复合物 III（9-HCX）来靶向癌细胞中的线粒体，如在分离的线粒体中所示。相应地，通过 Seahorse 测定法在 MDA-MB-231 细胞中分析到氧化线粒体呼吸（OXPHOS）受到抑制，线粒体质子泄漏增加，三磷酸腺苷（ATP）合成减少。因此，三萜烯基呫吨酮增加了线粒体超氧化物水平，诱导了线粒体膜通透性，并在 MDA-MB-231 三阴性乳腺癌细胞中引发了 caspase 3/7 介导的细胞凋亡。因此，来自藤黄的三萜烯基呫吨酮基于干扰线粒体呼吸表现出抗癌活性。
