School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China.
Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China.
Mol Med Rep. 2024 Nov;30(5). doi: 10.3892/mmr.2024.13330. Epub 2024 Sep 20.
Lung cancer has the highest incidence and mortality rates of all cancer types in China and therefore represents a serious threat to human health. In the present study, the mechanism of rabdoternin E against the proliferation of the lung cancer cell line A549 was explored. It was found that rabdoternin E caused the accumulation of large amounts of reactive oxygen species (ROS), promoted cell S phase arrest by reducing the expression of CDK2 and cyclin A2, induced apoptosis by increasing the Bax/Bcl‑2 ratio and promoted the phosphorylation of proteins in the ROS/p38 MAPK/JNK signaling pathway, which is associated with apoptosis and ferroptosis. In addition, it was also found that Z‑VAD‑FMK (an apoptosis inhibitor), ferrostatin‑1 (ferroptosis inhibitor) and N‑acetylcysteine (a ROS inhibitor) could partially or greatly reverse the cytotoxicity of rabdoternin E to A549 cells. Similarly, NAC (N‑acetylcysteine) treatment notably inhibited the rabdoternin E‑stimulated p38 MAPK and JNK activation. Furthermore, experiments in mice revealed that Rabdoternin E markedly reduced tumor volume and weight and regulated the expression levels of apoptosis and ferroptosis‑related proteins (including Ki67, Bcl‑2, Bax, glutathione peroxidase 4, solute carrier family 7 member 11 and transferrin) in the tumor tissues of mice. Histopathological observation confirmed that the number of tumor cells decreased markedly after administration of rabdoternin E. Taken together, rabdoternin E induced apoptosis and ferroptosis of A549 cells by activating the ROS/p38 MAPK/JNK signaling pathway. Therefore, the results of the present study showed that rabdoternin E is not toxic to MCF‑7 cells (normal lung cells), had no significant effect on body weight and was effective and therefore may be a novel therapeutic treatment for lung cancer.
在中国，肺癌的发病率和死亡率均居所有癌症类型之首，因此严重威胁着人类的健康。本研究旨在探讨拉波替尼对肺癌 A549 细胞增殖的作用机制。结果发现，拉波替尼导致大量活性氧（ROS）的积累，通过降低 CDK2 和细胞周期蛋白 A2 的表达来促进细胞 S 期停滞，通过增加 Bax/Bcl-2 比值诱导细胞凋亡，并通过激活 ROS/p38 MAPK/JNK 信号通路促进蛋白质磷酸化，与细胞凋亡和铁死亡有关。此外，还发现 Z-VAD-FMK（凋亡抑制剂）、ferrostatin-1（铁死亡抑制剂）和 N-乙酰半胱氨酸（ROS 抑制剂）可部分或极大地逆转拉波替尼对 A549 细胞的细胞毒性。同样，NAC（N-乙酰半胱氨酸）处理显著抑制拉波替尼刺激的 p38 MAPK 和 JNK 激活。此外，在小鼠实验中发现，拉波替尼显著降低了肿瘤体积和重量，并调节了肿瘤组织中与细胞凋亡和铁死亡相关的蛋白（包括 Ki67、Bcl-2、Bax、谷胱甘肽过氧化物酶 4、溶质载体家族 7 成员 11 和转铁蛋白）的表达水平。组织病理学观察证实，给予拉波替尼后肿瘤细胞数量明显减少。综上所述，拉波替尼通过激活 ROS/p38 MAPK/JNK 信号通路诱导 A549 细胞凋亡和铁死亡。因此，本研究结果表明，拉波替尼对 MCF-7 细胞（正常肺细胞）无毒性，对体重无显著影响，且具有疗效，因此可能是一种新型的肺癌治疗方法。
