Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells

Abstract

BackgroundItraconazole has been proved therapeutically effective against a variety of human cancers. This study assessed the effect of itraconazole on the Hedgehog (Hh) pathway and proliferation of human gastric cancer cells.MethodsCCK-8 assay and colony formation assay were used to assess the effects of itraconazole on proliferation of gastric cancer cells. The expression of Hh signaling components in gastric cancer cells treated with itraconazole was evaluated by reverse-transcription polymerase chain reaction, immunoblotting and dual luciferase assay. Tumor xenograft models were used to assess the inhibitory effect of itraconazole on the proliferation of gastric cancer cells in vivo.ResultsItraconazole could remarkably inhibit the proliferation of gastric cancer cells. When in combination with 5-FU, itraconazole significantly reduced the proliferation rate of cancer cells. Furthermore, itraconazole could regulate the G1-S transition and induce apoptosis of gastric cancer cells. Hh signaling was abnormally activated in human gastric cancer samples. In vitro, studies showed that the expression of glioma-associated zinc finger transcription factor 1 (Gli1) was decreased at both transcriptional and translational levels after treatment with itraconazole. Dual luciferase assay also indicated that itraconazole could inhibit the transcription of Gli1. In vivo studies demonstrated that monotherapy with itraconazole by oral administration could inhibit the growth of xenografts, and that itraconazole could significantly enhance the antitumor efficacy of the chemotherapeutic agent 5-FU.ConclusionsHh signaling is activated in gastric tumor and itraconazole can inhibit the growth of gastric cancer cells by inhibiting Gli1 expression.

RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis

“…In the etiology of GC, it has been confirmed that GLI1 is involved in H. pylori infection and promotes chronic information ( 24 , 25 ). Furthermore, the mechanism through which GLI1 enhances GC development involves many oncogenes, such as NAPDH oxidase 4 ( 26 ), Mucin 5AC, Oligomeric Mucus/Gel-Forming ( 27 ), and Wnt proteins ( 28 ), leading to increased resistance to chemotherapy drugs ( 29 , 30 ). Recently, it was shown that Hh signaling via Smoothened and GLI1 requires involvement of the RAB family ( 31 ).…”

Epoxymicheliolide, a novelguaiane-type sesquiterpene lactone, inhibits NF‑κB/COX‑2 signaling pathways by targeting leucine�281 and leucine�25 in IKKβ in renal cell carcinoma

“…As changes in cell proliferation are usually accompanied by changes in the cell cycle ( 28 ), the present study next evaluated the effect of EMCL on the cell cycle. As shown in Fig.…”

Cytotoxic and Genotoxic Effects of Fluconazole on African Green Monkey Kidney (Vero) Cell Line

“…For example, through flow cytometry and western blot analysis, Chen et al [ 23 ] observed that ketoconazole was able to induce growth arrest in G0/G1 phase in three cancer cells (COLO 205, Hep G2, and HT 29), which is probably due to decrease in cyclin D3 and CDK4 proteins. Itraconazole showed similar effects in gastric cancer cells [ 24 ]. Fluconazole-induced MN was also observed in newborn pups after transplacental exposure [ 25 , 26 ].…”