Lenvatinib induces anticancer activity in gallbladder cancer by targeting AKT

Abstract

Gallbladder cancer (GBC) is characterized by poor prognosis, early metastasis, and high recurrence rates, which seriously threaten human health. The effect of lenvatinib, a widely used drug in anti-hepatocellular carcinoma in China, on GBC progress, as well as its underlying molecular mechanism, remains unclear. Therefore, the present study investigated the effect of lenvatinib on human GBC GBC-SD and NOZ cells and its underlying mechanisms. A series of experiments, including cell proliferation, clone formation, wound healing, and cell migration and invasion assays, as well as flow cytometry, were performed to investigate the anticancer effect of lenvatinib on GBC. Western blotting was used to detect alterations in protein expression of CKD2, CKD4, cyclin D1, caspase-9, matrix metalloproteinase (MMP)-2, cell migration-inducing protein (CEMIP) and phospho-AKT (p-AKT). In addition, the chemosensitivity of lenvatinib-treated GBC cells to gemcitabine (GEM) and whether the activation of phosphoinositide 3 kinase (PI3K)/AKT contributed to the chemoresistance were determined. Finally, the anticancer effect of lenvatinib in vivo was detected using a xenograft mouse model. These data showed that treatment with lenvatinib inhibited cell proliferation, colony formation ability, migration, induced apoptosis, regulated cell cycle and resulted in decreased resistance to GEM. Treatment with lenvatinib decreased the expression of MMP-2, CEMIP, CDK2, CDK4 and cyclin D1, and increased the expression of cleaved caspase-9, which was mediated by the inactivation of the PI3K/AKT pathway in vitro. In addition, lenvatinib inhibited autophagy in GBC-SD and NOZ cells. Besides, Lenvatinib suppressed GBC cell growth in vivo by targeting p-AKT. In combination, the present data indicated that lenvatinib plays a potential anticancer role in GBC by downregulating the expression of p-AKT.

[Retracted] Antigallbladder Carcinoma Activity Analysis of a New Nanometer Drug Delivery System Based on Data Acquisition

“…The chance of radical treatment is lost, resulting in a poor prognosis [ 19 ]. There is no clear etiology of gallbladder carcinoma, but epidemiology shows that it is related to the presence of gallstones [ 20 ].…”

Role of CYCLIN D1, E-Cadherin, EGFR, Her-2, KI67, and P53 Expressions as Prognostic Markers in Gall Bladder Cancer

“…In addition to these factors, cyclin D1 overexpression can be caused by alterations of associated signalling intermediates, including the RAS-MEK-ERK and PI3K pathways [13]. While several studies on drugs targeting Cyclin D1 regulation have been made [14,15,16], its role as a prognostic marker in GBC is yet to be established and warrants further investigation. Assessment of the complex contributory role played by Cyclin D1 in carcinogenesis and tumour progression could enable the development of effective personalized therapies through proper prognosis and accurate staging of GBC.…”

Recent advances in chemistry and therapeutic potential of functionalized quinoline motifs – a review

“…92 This is because they are the three most crucial growth factor receptors with direct implication in cancerous cell lines. 93 Some designed quinoline-based inhibitors used in the treatment of different types of cancers are lenvatinib 73 , 94 tivozanib, 74 , 95 Ki8751 75 , 96 pelitinib 76 , 97 neratinib 77 , 98 pyrotinib 78 , 99,100 cabozantinib 32 , 101,102 and foretinib 33 . 103 They are ligands with good binding affinity to these growth factor receptors, selectively or collectively.…”