Laboratório de Genética Toxicológica, Universidade Estadual de Londrina, PR, Brazil.
Laboratório de Genética Toxicológica, Universidade Estadual de Londrina, PR, Brazil.
Life Sci. 2023 Oct 1;330:122033. doi: 10.1016/j.lfs.2023.122033. Epub 2023 Aug 19.
Aim Overcoming resistance to apoptosis and antimitotic chemotherapy is crucial for effective treatment of lung cancer. Diosgenin (DG), a promising phytochemical, can regulate various molecular pathways implicated in tumor formation and progression. However, the precise biological activity of DG in lung cancer remains unclear. This study aimed to investigate the antiproliferative activity of DG in NCI-H460 lung carcinoma cells to explore the underlying antimitotic mechanisms and alternative cell death pathways.
In a 2D culture system, we analyzed cell viability, multinucleated cell frequency, cell concentration, cell cycle changes, cell death induction, intracellular reactive oxygen species (ROS) production, and nuclear DNA damage, particularly in relation to target gene expression. We also evaluated the antiproliferative activity of DG in a 3D culture system of spheroids, assessing volume changes, cell death induction, and inhibition of proliferation recovery and clonogenic growth.
DG reduced cell viability and concentration while increasing the frequency of cells with multiple nuclei, particularly binucleated cells resulting from daughter cell fusion. This effect was associated with genes involved in cytokinesis regulation (RAB35, OCRL, BIRC5, and AURKB). Additionally, DG-induced cell death was linked to necroptosis, as evidenced by increased intracellular ROS production and RIPK3, MLKL, TRAF2, and HSPA5 gene expression. In tumor spheroids, DG increased spheroid volume, induced cell death, and inhibited proliferation recovery and clonogenic growth.
Our study provides new insights into the biological activities of DG in lung cancer cells, contributing to the development of novel oncological therapies.
克服细胞凋亡和抗有丝分裂化疗的抗性对于肺癌的有效治疗至关重要。薯蓣皂苷元（DG）是一种有前途的植物化学物质，可以调节与肿瘤形成和进展相关的各种分子途径。然而，DG 在肺癌中的精确生物学活性尚不清楚。本研究旨在研究 DG 在 NCI-H460 肺癌细胞中的抗增殖活性，以探索潜在的抗有丝分裂机制和替代细胞死亡途径。
在 2D 培养系统中，我们分析了细胞活力、多核细胞频率、细胞浓度、细胞周期变化、细胞死亡诱导、细胞内活性氧（ROS）产生和核 DNA 损伤，特别是与靶基因表达的关系。我们还评估了 DG 在球体的 3D 培养系统中的抗增殖活性，评估体积变化、细胞死亡诱导以及抑制增殖恢复和克隆形成生长。
DG 降低了细胞活力和浓度，同时增加了具有多个核的细胞的频率，特别是来自子细胞融合的双核细胞。这种作用与涉及胞质分裂调节的基因有关（RAB35、OCRL、BIRC5 和 AURKB）。此外，DG 诱导的细胞死亡与坏死性凋亡有关，这表现为细胞内 ROS 产生增加以及 RIPK3、MLKL、TRAF2 和 HSPA5 基因表达增加。在肿瘤球体中，DG 增加了球体的体积，诱导了细胞死亡，并抑制了增殖恢复和克隆形成生长。
本研究为 DG 在肺癌细胞中的生物学活性提供了新的见解，为开发新的肿瘤治疗方法做出了贡献。
