Kim Jae-Yoon, Kim Yejin, Woo Soo-Yeon, Kim Jin-Ok, Kim Hyunsoo, Son So-Ri, Jang Dae Sik, Choi Jung-Hye
Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
Antioxidants (Basel). 2025 Jul 10;14(7):846. doi: 10.3390/antiox14070846.
Ovarian cancer, the most lethal form of gynecological cancer worldwide with a poor prognosis, is largely driven by an immunosuppressive tumor microenvironment. In this study, we investigated the anticancer effects of hydnocarpin, a natural flavonolignan derived from the flowers of , focusing on its effects on ovarian cancer and tumor-associated immune cells, including ovarian cancer-stimulated macrophages (MQs) and T cells. Hydnocarpin exhibited potent cytotoxicity against multiple ovarian cancer cell lines but only minimal toxicity against normal ovarian surface epithelial cells. Mechanistically, hydnocarpin triggered caspase-dependent apoptosis, as evidenced by the activation of caspase-9 and -3, with limited involvement of caspase-8, indicating the activation of the intrinsic apoptotic pathway. Experimental data implicated reactive oxygen species generation as a key mediator of hydnocarpin cytotoxicity, and reactive oxygen species inhibition significantly inhibited this cytotoxicity. In addition to its direct tumoricidal effects, hydnocarpin reprogrammed the tumor-associated immune cells, ovarian cancer-stimulated macrophages and T cells, by downregulating the levels of M2 MQ markers and pro-tumoral factors (matrix metalloproteinase-2/9, C-C motif chemokine ligand 5, transforming growth factor-β, and vascular endothelial growth factor) and enhancing MQ phagocytosis. Additionally, hydnocarpin promoted T-cell activation (interferon-γ and interleukin-2) and reduced the expression levels of immune evasion markers (CD80, CD86, and VISTA). Overall, this study demonstrated the dual anti-tumor effects of hydnocarpin on both ovarian cancer cells and immunosuppressive immune components in the tumor microenvironment, highlighting its potential as a novel therapeutic candidate for ovarian cancer.
卵巢癌是全球最致命的妇科癌症形式，预后较差，很大程度上由免疫抑制性肿瘤微环境驱动。在本研究中，我们研究了从[植物名称]花中提取的天然黄酮木脂素——大风子素的抗癌作用，重点关注其对卵巢癌和肿瘤相关免疫细胞的影响，包括卵巢癌刺激的巨噬细胞（MQs）和T细胞。大风子素对多种卵巢癌细胞系表现出强大的细胞毒性，但对正常卵巢表面上皮细胞的毒性极小。从机制上讲，大风子素触发了半胱天冬酶依赖性凋亡，这通过半胱天冬酶-9和-3的激活得以证明，而半胱天冬酶-8的参与有限，表明内在凋亡途径被激活。实验数据表明活性氧的产生是大风子素细胞毒性的关键介质，抑制活性氧可显著抑制这种细胞毒性。除了其直接的杀肿瘤作用外，大风子素还通过下调M2 MQ标志物和促肿瘤因子（基质金属蛋白酶-2/9、C-C基序趋化因子配体5、转化生长因子-β和血管内皮生长因子）的水平并增强MQ吞噬作用，对肿瘤相关免疫细胞、卵巢癌刺激的巨噬细胞和T细胞进行了重编程。此外，大风子素促进T细胞活化（干扰素-γ和白细胞介素-2）并降低免疫逃逸标志物（CD80、CD86和VISTA）的表达水平。总体而言，本研究证明了大风子素对卵巢癌细胞和肿瘤微环境中免疫抑制性免疫成分具有双重抗肿瘤作用，突出了其作为卵巢癌新型治疗候选药物的潜力。
