Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation Yantai University, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, China.
Neoplasma. 2023 Feb;70(1):58-70. doi: 10.4149/neo_2022_220418N423. Epub 2023 Jan 13.
Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human pulmonary alveolar epithelial cells (HPAEpiC), A549, and H460 cell lines were used to detect the efficacy of zerumbone. BALB/c nude mice were randomly divided into five groups, including model, gefitinib (Gef, 10 mg/kg), low dose zerumbone (L-Zer, 20 mg/kg), high dose zerumbone (H-Zer, 40 mg/kg), and H-Zer + Gef groups, and the tumor growth in each group was monitored. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect cell apoptosis. Immunohistochemistry (IHC), immunofluorescence, and western blot were used to analyze the protein expressions in tumor tissues. Glutathione (GSH) and malondialdehyde (MAD) were detected by special kits. Zerumbone inhibited the proliferation of lung cancer cells in vitro. Tumor volume and weight were reduced after gefitinib or zerumbone treatment. Gefitinib and zerumbone treatment significantly promoted the apoptosis of tumor cells. The expression of Bcl-2, Bax, and P53 proteins confirmed cell apoptosis. IHC results indicated that zerumbone and gefitinib treatment decreased tumor angiogenesis. Consistent with this result, the expression of EGFR, VEGFR2, and Ki-67 proteins decreased, while the expression of angiostatin and endostatin proteins increased. Interestingly, zerumbone treatment increased the level of MDA while decreasing GSH. Next, the levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased after zerumbone and gefitinib treatment. Our study suggested that zerumbone combined with gefitinib could effectively inhibit lung cancer for multi-model therapies, including the inhibition of tumor growth, angiogenesis, induce cell apoptosis, and ferroptosis.
姜烯酮已被证实为一种有潜力的抗癌药物。我们的研究旨在探究姜烯酮联合吉非替尼治疗肺癌的效果。采用人肺泡上皮细胞（HPAEpiC）、A549 和 H460 细胞系检测姜烯酮的功效。BALB/c 裸鼠随机分为 5 组，包括模型组、吉非替尼（Gef，10mg/kg）组、低剂量姜烯酮（L-Zer，20mg/kg）组、高剂量姜烯酮（H-Zer，40mg/kg）组和 H-Zer+Gef 组，监测各组肿瘤生长情况。TdT 介导的 dUTP 缺口末端标记（TUNEL）法检测细胞凋亡。免疫组化（IHC）、免疫荧光和 Western blot 分析肿瘤组织中的蛋白表达。采用特殊试剂盒检测谷胱甘肽（GSH）和丙二醛（MDA）。姜烯酮抑制肺癌细胞体外增殖。吉非替尼或姜烯酮治疗后肿瘤体积和重量减小。吉非替尼和姜烯酮治疗显著促进肿瘤细胞凋亡。Bcl-2、Bax 和 P53 蛋白表达证实细胞凋亡。IHC 结果表明姜烯酮和吉非替尼治疗减少肿瘤血管生成。与该结果一致，EGFR、VEGFR2 和 Ki-67 蛋白表达降低，而血管抑素和内皮抑素蛋白表达增加。有趣的是，姜烯酮治疗增加 MDA 水平，降低 GSH 水平。随后，姜烯酮和吉非替尼治疗后谷胱甘肽过氧化物酶 4（GPX4）和溶质载体家族 7 成员 11（SLC7A11）表达降低。本研究表明，姜烯酮联合吉非替尼可有效抑制肺癌，多模式治疗包括抑制肿瘤生长、血管生成、诱导细胞凋亡和铁死亡。
