Teleb Eman K, Mehanna Radwa A, Assem Nagwa M, Houssen Maha E
Biochemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22511, Egypt.
Medical Physiology, Faculty of Medicine, Alexanderia University, Alexanderia, Egypt.
Med Oncol. 2025 Apr 10;42(5):157. doi: 10.1007/s12032-025-02679-4.
The majority of lung cancer cases are non-small cell lung cancer (NSCLC) which continues to be a serious global health concern. Hypoxia-inducible factor (HIF-α) pathway is a promising therapeutic target because it has a vital function in advanced non-small cell lung carcinoma. Antiangiogenic multi-kinase inhibitor, sorafenib may have a part in regulating HIF signaling in cancer. As a result, there is now more interest in employing it to target hypoxia-driven pathways in non-small cell lung cancer, especially when paired with natural bioactive products such as dauricine which is a naturally occurring alkaloid molecule targets multiple cellular pathways to provide strong anticancer effects. To examine molecular impacts of combining dauricine with sorafenib on HIF-mediated signaling pathways in human lung cancer cell lines. Cell viability was assessed using MTT assay in A549 and H1975 lung tumor cell lines. Levels of key proteins (AKT, mTORC1, HIF-1 α, ERK, VEGF, Cyclin-D1, BCL2, and E-Cadherin) were measured by ELISA.A colorimetric test was utilized to assess the activity of caspase-3, as a marker of apoptosis. qRT-PCR was employed to identify PI3K and VEGFR2 genes expression. Combination of sorafenib and dauricine significantly enhanced cytotoxicity compared to either agent alone. This combination also led to a marked reduction in VEGFR2, PI3K expression and VEGF, AKT, mTOR, HIF-1α, BCL2, ERK and E-Cadherin, and Cyclin-D1 levels. In addition, there was a significant increase in caspase-3 activity. Dauricine potentiates antitumor effects of sorafenib in human NSCLC by modulating HIF-1α-mediated pathways that are involved in several cancer hallmarks. This combination shows promise as a potential lung cancer treatment approach.
大多数肺癌病例是非小细胞肺癌（NSCLC），它仍然是一个严重的全球健康问题。缺氧诱导因子（HIF-α）通路是一个有前景的治疗靶点，因为它在晚期非小细胞肺癌中具有重要作用。抗血管生成多激酶抑制剂索拉非尼可能参与调节癌症中的HIF信号传导。因此，现在人们对将其用于靶向非小细胞肺癌中缺氧驱动的通路更感兴趣，特别是与天然生物活性产物如蝙蝠葛碱联合使用时，蝙蝠葛碱是一种天然存在的生物碱分子，可靶向多种细胞通路以提供强大的抗癌作用。为了研究蝙蝠葛碱与索拉非尼联合对人肺癌细胞系中HIF介导的信号通路的分子影响。在A549和H1975肺肿瘤细胞系中使用MTT法评估细胞活力。通过ELISA测量关键蛋白（AKT、mTORC1、HIF-1α、ERK、VEGF、细胞周期蛋白D1、BCL2和E-钙黏蛋白）的水平。采用比色试验评估作为凋亡标志物的半胱天冬酶-3的活性。使用qRT-PCR鉴定PI3K和VEGFR2基因的表达。与单独使用任何一种药物相比，索拉非尼和蝙蝠葛碱的联合显著增强了细胞毒性。这种联合还导致VEGFR2、PI3K表达以及VEGF、AKT、mTOR、HIF-1α、BCL2、ERK和E-钙黏蛋白以及细胞周期蛋白D1水平显著降低。此外，半胱天冬酶-3活性显著增加。蝙蝠葛碱通过调节参与多种癌症特征的HIF-1α介导的通路增强索拉非尼对人非小细胞肺癌的抗肿瘤作用。这种联合显示出作为一种潜在肺癌治疗方法的前景。
