Hedyotis diffusa injection induces ferroptosis via the Bax/Bcl2/VDAC2/3 axis in lung adenocarcinoma
Hedyotis diffusa injection induces ferroptosis via the Bax/Bcl2/VDAC2/3 axis in lung adenocarcinoma
复制标题
白花蛇舌草注射液通过Bax/Bcl2/VDAC2/3轴诱导肺腺癌铁下垂
DOI：
10.1016/j.phymed.2022.154319
复制
发表时间：
2022-07-16
期刊：
影响因子：
7.9
通讯作者：
Li, Xian
中科院分区：
文献类型：
--
作者：
Huang, Fuhao;Pang, Jinlong;Li, Xian
背景：肺癌在所有癌症类型中死亡率最高。目的：研究白花蛇舌草（Hedyotis diffusa，HDI）对肺腺癌细胞株和BALB/c裸鼠移植瘤模型的作用，探讨HDI是否能诱导肺腺癌细胞沿着出现铁凋亡，并探讨其作用机制。HDI的抗肿瘤活性通过细胞计数试剂盒-8、克隆形成和transwell测定法在体外测定。随后，进行电子显微镜、脂质活性氧测定、亚铁离子染色和丙二醛测定以确定对肺腺癌细胞中铁凋亡的影响。然后使用小分子抑制剂、siRNA和质粒过表达在体外进一步研究该机制。结果：体外实验表明，HDI可抑制肺腺癌细胞的生长，诱导肺腺癌细胞铁凋亡，其机制与VDAC 2/3密切相关，与GPX 4和PUFA-PLS途径无关。HDI通过抑制Bcl 2而促进Bax的表达，从而调节VDAC 2/3的活性，诱导肺腺癌细胞的铁凋亡。体内实验表明，HDI能显著抑制BALB/c裸鼠皮下肿瘤的生长，且对器官损伤和毒性较小，并能显著增加肿瘤组织中铁凋亡相关指标4 HNE、TFR和HMOX 1的表达。HDI可显著降低肺腺癌细胞的体外存活率，在体内抑制BALB/c裸鼠皮下移植瘤的生长，并通过Bcl 2抑制促进Bax对VDAC 2/3的调节诱导肺腺癌细胞的铁凋亡。
Background: Lung cancer has the highest mortality rate among all cancer types. In combination with multiple chemotherapeutic options, traditional Chinese medicine has proven indispensable for the comprehensive treatment of lung cancer.Purpose: To investigate the effects of Hedyotis diffusa on lung adenocarcinoma cell lines and a BALB/c nude mouse xenograft model, and determine whether HDI could induce ferroptosis in lung adenocarcinoma cells along with the underlying mechanism.Methods: The anti-tumor activity of HDI was determined in vitro by cell counting kit-8, clonogenic, and transwell assays. Subsequently, electron microscopy, a lipid reactive oxygen species assay, ferrous ion staining, and a malondialdehyde assay were performed to determine the effect on ferroptosis in lung adenocarcinoma cells. The mechanism was then further investigated using small molecule inhibitors, siRNA, and plasmid overexpression in vitro. Finally, the effects of HDI were assessed in tumor-bearing BALB/c nude mice, and HE staining was performed to observe tissue damage after HDI treatment.Results: In vitro experiments showed that HDI could inhibit the viability of lung adenocarcinoma cells and induce lung adenocarcinoma cells ferroptosis via mechanisms independent of GPX4 and PUFA-PLS pathways but closely associated with VDAC2/3. HDI regulated VDAC2/3 activity by promoting Bax via inhibiting Bcl2, thereby inducing ferroptosis in lung adenocarcinoma cells. Furthermore, in vivo experiments showed that HDI significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice with less organ damage and toxicity, and significantly increased the expression of the ferroptosis-related indicators 4HNE, TFR, and HMOX1 in tumor tissue.Conclusion: HDI can significantly reduce the survival of lung adenocarcinoma cells in vitro, inhibit the growth of subcutaneously transplanted tumors in BALB/c nude mice in vivo, and induce ferroptosis in lung adenocarcinoma cells via Bcl2 inhibition to promote Bax regulation of VDAC2/3.