School of Pharmacy, Bengbu Medical College, Bengbu City 233000, China.
School of Pharmacy, Bengbu Medical College, Bengbu City 233000, China.
Phytomedicine. 2022 Sep;104:154319. doi: 10.1016/j.phymed.2022.154319. Epub 2022 Jul 8.
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.
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.
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.
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.
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.
肺癌是所有癌症类型中死亡率最高的。结合多种化疗选择，中药对于肺癌的综合治疗已被证明是不可或缺的。
研究白花蛇舌草（Hedyotis diffusa）对肺腺癌细胞系和 BALB/c 裸鼠异种移植模型的作用，并确定 HDI 是否可以通过诱导肺腺癌细胞发生铁死亡以及潜在机制来发挥作用。
通过细胞计数试剂盒-8、集落形成和 Transwell 测定法在体外测定 HDI 的抗肿瘤活性。随后，通过电子显微镜、脂质活性氧物种测定法、亚铁离子染色和丙二醛测定法来确定其对肺腺癌细胞铁死亡的影响。然后，通过小分子抑制剂、siRNA 和质粒过表达在体外进一步研究其机制。最后，在荷瘤 BALB/c 裸鼠中评估了 HDI 的作用，并进行 HE 染色以观察 HDI 处理后的组织损伤。
体外实验表明，HDI 可以通过与 GPX4 和 PUFA-PLS 途径无关但与 VDAC2/3 密切相关的机制抑制肺腺癌细胞的活力并诱导肺腺癌细胞铁死亡。HDI 通过抑制 Bcl2 来促进 Bax 的表达，从而调节 VDAC2/3 的活性，进而诱导肺腺癌细胞发生铁死亡。此外，体内实验表明，HDI 显著抑制了 BALB/c 裸鼠皮下移植瘤的生长，且对器官的损伤和毒性较小，并显著增加了肿瘤组织中与铁死亡相关的指标 4HNE、TFR 和 HMOX1 的表达。
HDI 可显著降低肺腺癌细胞在体外的存活率，抑制 BALB/c 裸鼠体内皮下移植瘤的生长，并通过抑制 Bcl2 促进 Bax 调节 VDAC2/3 来诱导肺腺癌细胞发生铁死亡。
