Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile.
Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia 5090000, Chile.
Int J Mol Sci. 2024 Oct 29;25(21):11601. doi: 10.3390/ijms252111601.
Lung cancer (LC) is the leading cause of cancer death worldwide. LC can be classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with the last subtype accounting for approximately 85% of all diagnosed lung cancer cases. Despite the existence of different types of treatment for this disease, the development of resistance to therapies and tumor recurrence in patients have maintained the need to find new therapeutic options to combat this pathology, where natural products stand out as an attractive source for this search. Nordihydroguaiaretic acid (NDGA) is the main metabolite extracted from the Larrea tridentata plant and has been shown to have different biological activities, including anticancer activity. In this study, H1975, H1299, and A549 cell lines were treated with NDGA, and its effect on cell viability, proliferation, and metabolism was evaluated using a resazurin reduction assay, incorporation of BrdU, and ki-67 gene expression and glucose uptake measurement, respectively. In addition, the combination of NDGA with clinical chemotherapeutics was investigated using an MTT assay and Combenefit software (version 2.02). The results showed that NDGA decreases the viability and proliferation of NSCLC cells and differentially modulates the expression of genes associated with different metabolic pathways. For example, the LDH gene expression decreased in all cell lines analyzed. However, GLUT3 gene expression increased after 24 h of treatment. The expression of the HIF-1 gene decreased early in the H1299 and A549 cell lines. In addition, the combination of NDGA with three chemotherapeutics (carboplatin, gemcitabine, and taxol) shows a synergic pattern in the decrease of cell viability on the H1299 cell line. In summary, this research provides new evidence about the role of NDGA in lung cancer. Interestingly, using NDGA to enhance the anticancer activity of antitumoral drugs could be an improved therapeutic resource against lung cancer.
肺癌（LC）是全球癌症死亡的主要原因。LC 可分为小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC），后者约占所有诊断为肺癌病例的 85%。尽管针对这种疾病存在不同类型的治疗方法，但患者对治疗的耐药性和肿瘤复发的发展仍然需要寻找新的治疗选择来对抗这种病理学，其中天然产物作为这种搜索的一个有吸引力的来源脱颖而出。去甲二氢愈创木酸（NDGA）是从 Larrea tridentata 植物中提取的主要代谢物，已显示出具有不同的生物学活性，包括抗癌活性。在这项研究中，用 NDGA 处理 H1975、H1299 和 A549 细胞系，并用 Resazurin 还原测定、BrdU 掺入、ki-67 基因表达和葡萄糖摄取测量分别评估其对细胞活力、增殖和代谢的影响。此外，还使用 MTT 测定法和 Combenefit 软件（版本 2.02）研究了 NDGA 与临床化疗药物的联合使用。结果表明，NDGA 降低了 NSCLC 细胞的活力和增殖，并差异调节与不同代谢途径相关的基因表达。例如，所有分析的细胞系中 LDH 基因表达降低。然而，治疗 24 小时后 GLUT3 基因表达增加。H1299 和 A549 细胞系中 HIF-1 基因的表达早期下降。此外，NDGA 与三种化疗药物（卡铂、吉西他滨和紫杉醇）的联合在 H1299 细胞系中降低细胞活力方面表现出协同模式。总之，这项研究提供了关于 NDGA 在肺癌中的作用的新证据。有趣的是，使用 NDGA 增强抗肿瘤药物的抗癌活性可能是改善针对肺癌的治疗资源。
