Abstract
Anlotinib (AL3818), a novel multi-targeted receptor tyrosine kinase inhibitor, has recently been proven to be an antitumour drug. This study aimed to explore the antitumour effect of anlotinib and its underlying molecular mechanisms in human pancreatic cancer (PC) cells. The anti-proliferative effect of anlotinib for three PC cell lines was validated using CCK-8, colony formation and EdU detection assays. Cell cycle, cell apoptosis, and reactive oxygen species (ROS) detection assays, a PC xenograft model and immunohistochemistry were performed to elucidate the mechanisms by which anlotinib induced tumour lethality in vitro and in vivo. These results demonstrated that anlotinib inhibited proliferation, induced G2/M phase arrest and triggered apoptosis in PC cell lines. Anlotinib induced PC’s apoptosis through the accumulation of ROS which activated the endoplasmic reticulum (ER) stress via PERK/p-eIF2α/ATF4 pathway. Furthermore, we demonstrated that the expression level of Nrf2, an antioxidant protein, increased with anlotinib treatment. Nrf2 knockdown enhanced the pro-apoptotic effect of anlotinib and the expression of the PERK/p-eIF2α/ATF4 pathway. The in vivo results suggested that suppressing Nrf2 improved the antitumour effect of anlotinib on PC cells. These data indicated that the apoptotic effect of anlotinib on PC cells was induced by ER stress via the accumulation of ROS. In the future, anlotinib combined with an Nrf2 inhibitor may provide a new therapeutic strategy for the treatment of human PC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) results in more than 90% of all types of pancreatic cancers (PC) and is predicted to be the third leading cause of cancer death in the decade[1,2]
The morphological changes in PC cells cultured with increasing concentrations of anlotinib were observed under a microscope
The EdU detection assay at 24 h showed that the percentage of labelled cells decreased in the PANC-1, BxPC-3 and SW1990 cell lines as the concentration of anlotinib increased (Fig. 1f-i)
Summary
Pancreatic ductal adenocarcinoma (PDAC) results in more than 90% of all types of pancreatic cancers (PC) and is predicted to be the third leading cause of cancer death in the decade[1,2]. It was initially designed to inhibit vascular endothelial growth factor receptor (VEGFR) but is reported to affect other tumour proliferation-related receptor tyrosine kinases, including platelet-derived growth factor α and β, Ret, c-kit, fibroblast growth factor receptor (FGFR) and so forth[6]. Clinical trials of this drug in various cancers, such as sarcoma[7], renal cell carcinoma[8] and colorectal tumours[9], are under development.
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