Antitumor effects of dauricine on sorafenib-treated human lung cancer cell lines via modulation of HIF-1α signaling pathways

Abstract

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.