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Hydnocarpin, a Natural Flavonolignan, Induces the ROS-Mediated Apoptosis of Ovarian Cancer Cells and Reprograms
Jae-Yoon Kim1, Yejin Kim1, Soo-Yeon Woo1
1Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
Abstract:
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 Pueraria lobata, 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.
Insights
Hydnocarpin, a natural compound, effectively kills ovarian cancer cells by inducing apoptosis and reprogramming immunosuppressive immune cells. This dual action highlights its potential as a novel ovarian cancer therapy.
Area of Science:
- Oncology
- Immunology
- Natural Product Chemistry
Background:
- Ovarian cancer is a lethal gynecological malignancy with a poor prognosis, often driven by an immunosuppressive tumor microenvironment.
- Natural compounds are being explored for their therapeutic potential against cancer.
Purpose of the Study:
- To investigate the anticancer effects of hydnocarpin, a natural flavonolignan from Pueraria lobata, on ovarian cancer cells and the tumor microenvironment.
- To elucidate the mechanisms underlying hydnocarpin's anti-ovarian cancer activity, including its impact on immune cells.
Main Methods:
- Cytotoxicity assays were performed on ovarian cancer cell lines and normal epithelial cells.
- Apoptosis was assessed via caspase activation and reactive oxygen species (ROS) generation.
- Immunomodulatory effects were evaluated by analyzing macrophage and T-cell markers and functions.
Main Results:
- Hydnocarpin demonstrated potent cytotoxicity against ovarian cancer cells with minimal toxicity to normal cells.
- The compound induced caspase-dependent apoptosis through the intrinsic pathway, mediated by ROS generation.
- Hydnocarpin reprogrammed immunosuppressive macrophages and promoted T-cell activation while reducing immune evasion markers.
Conclusions:
- Hydnocarpin exhibits dual anti-tumor effects by directly killing ovarian cancer cells and modulating the immunosuppressive tumor microenvironment.
- These findings suggest hydnocarpin holds promise as a novel therapeutic candidate for ovarian cancer treatment.
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