Babaei Zeinab, Ghanadian Mustafa, Aghaei Mahmoud
Department of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Department of Pharmacognosy, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Science, Isfahan, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 28. doi: 10.1007/s00210-025-04085-z.
Phytochemical analysis of the aerial parts of Centaurea schmidii Wagenitz (Asteraceae) led to the isolation of disafynol, a novel polyacetylene, for the first time. This study investigated its anti-cancer effects and the mechanisms underlying these effects in MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive) breast cancer cell lines. The cytotoxic effects of disafynol were evaluated using various concentrations to measure cell viability, apoptosis, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), caspases-12/6 activity, and protein aggregation. Expression of apoptotic markers and endoplasmic reticulum (ER) stress-related genes was analyzed by western blot and reverse transcription-PCR analyses, respectively. Disafynol exhibited dose-dependent cytotoxicity, with greater potency in MDA-MB-231 cells (IC50: 10.6 µM) compared to MCF-7 cells (IC50: 30 µM), indicating hormone receptor-independent manner of cell growth inhibition. Treating cells with disafynol caused significant apoptosis, marked by enhanced ROS production and reduced MMP. Meanwhile, disafynol induced Bcl-2 downregulation, Bax upregulation, and caspase-12/6 activities in both breast cancer cells. Additionally, disafynol triggered ER stress, as evidenced by protein aggregation and upregulation of genes related to ER stress, including BIP, ATF4, CHOP, and XBP-1. Overall, disafynol demonstrates significant pro-apoptotic effects on breast cancer cells by inducing oxidative stress and activating the ER stress pathway. Its hormone receptor-independent cytotoxicity suggests potential therapeutic applications for treating breast cancers, including triple-negative subtypes.
对施密德矢车菊（菊科）地上部分进行的植物化学分析首次分离出了一种新型聚乙炔——二沙酚。本研究调查了其对MDA-MB-231（雌激素受体阴性）和MCF-7（雌激素受体阳性）乳腺癌细胞系的抗癌作用及其作用机制。使用不同浓度的二沙酚评估其细胞毒性作用，以测量细胞活力、凋亡、活性氧（ROS）水平、线粒体膜电位（MMP）、半胱天冬酶-12/6活性和蛋白质聚集情况。分别通过蛋白质印迹法和逆转录-PCR分析来分析凋亡标志物和内质网（ER）应激相关基因的表达。二沙酚表现出剂量依赖性细胞毒性，与MCF-7细胞（IC50：30 μM）相比，在MDA-MB-231细胞中效力更强（IC50：10.6 μM），表明其以激素受体非依赖性方式抑制细胞生长。用二沙酚处理细胞会导致显著凋亡，其特征为ROS生成增加和MMP降低。同时，二沙酚在两种乳腺癌细胞中均诱导Bcl-2下调、Bax上调以及半胱天冬酶-12/6活性增加。此外，二沙酚引发了ER应激，蛋白质聚集以及与ER应激相关基因（包括BIP、ATF4、CHOP和XBP-1）的上调证明了这一点。总体而言，二沙酚通过诱导氧化应激和激活ER应激途径，对乳腺癌细胞表现出显著的促凋亡作用。其激素受体非依赖性细胞毒性表明其在治疗包括三阴性亚型在内的乳腺癌方面具有潜在的治疗应用价值。
