Wnt inhibitor XAV939 suppresses the viability of small cell lung cancer NCI‑H446 cells and induces apoptosis

Abstract

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer due to a fast tumor doubling time and early hematogenous spread. Advances in the treatment of non-small cell lung cancer using targeted therapies having been made, but no targeted drugs for SCLC have been approved. The Wnt signaling pathway is associated with tumor progression and metastasis; therefore, the inhibition of Wnt/β-catenin signaling is a strategy for anticancer drugs. Tankyrase 1 (TNKS1) is overexpressed in a number of types of cancer and XAV939 is a small molecule inhibitor of TNKS1 which may inhibit tumor growth. The present study aimed to investigate the potential molecular mechanisms underlying XAV939-induced suppression of the viability of SCLC cells. MTT assays were used to determine the viability-inhibition rate of cells and to identify the drug concentration which optimally inhibited cell viability. Flow cytometry was used to determine whether XAV939 induced apoptosis of SCLC cells, and to analyze the effect of the drug on the cell cycle. The results of the present study identified that XAV939 inhibited the viability of NCI-H446 cells in a dose-dependent manner, but cisplatin inhibited NCI-H446 cell viability in a time- and dose-dependent manner. The combination of XAV939 and cisplatin exhibited a slightly more pronounced inhibition of cell viability at an increased dose of XAV939. In addition, XAV939 markedly induced cell apoptosis of the SCLC cell line H446 by increasing the proportion of cells in the G0/G1 phase, leading to inhibition of the cell cycle. The results of the present study indicated that XAV939 inhibited the viability of the NCI-H446 SCLC cell line by inducing cell apoptosis through the Wnt signaling pathway. Therefore, XAV939 may be useful for the treatment of SCLC.

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

“…Currently, there are several ongoing clinical trials of Wnt signalling pathway inhibitors that have been used to restrain tumour growth. XAV939 is a small molecule TNKS inhibitor targeting Wnt signalling pathway, which inhibits the abnormal activation of Wnt/b-catenin without affecting the normal function of cells [21,22]. Therefore, XAV939 is considered as a potential adjuvant to radiotherapy.…”

“…Studies have shown Wnt/b-catenin signalling is often upregulated in a variety of cancer, which endows cells with a stem-like phenotype that enhances self-renewal ability, multi-differential potential, and induces epithelial-to-mesenchymal transition of cancer cells [21]. Moreover, aberrant activation of canonical Wnt signalling is usually associated with cancer cell-elicited immunosuppression, metastasis, and increased cancer cell tolerance to chemo/ radiotherapy or hormonal therapy [21,22]. Previous studies showed that activation of the Wnt/b-catenin signalling pathway may play a key role in the progression of cervical cancer following persistent HPV infection [23].…”

“…XAV939 was characterized as a small molecule inhibitor of Wnt signalling pathway, which could block Wnt signalling in cancer cell lines through binding to tankyrase (TNKS) catalytic poly-ADP-ribose polymerase (PARP) domain, in turn, results in dramatic stabilization of the Axin protein, thereby leads to inhibition of transcription regulated by b-catenin [24,25]. Besides, compared with other Wnt pathway inhibitors, XAV939 has a strong specificity for the Wnt signalling pathway without affecting NF-jB or TGF-b signalling pathways [22]. Therefore, XAV939 may be a potential radiosensitizer for the treatment of tumours.…”

MicroRNA-552 promotes hepatocellular carcinoma progression by downregulating WIF1

“…As expected, miR-552 knockdown decreased GSK3β phosphorylation and β-catenin expression. XAV939 has been previously confirmed as an inhibitor of β-catenin ( 26 ). In the present study, XAV939 was used to treat Hep3B cells with miR-552 overexpression.…”

Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks

“…Mouse tumor xenografts with triple-negative breast cancer were incubated with paclitaxel-combined XAV939 regimen which induced cell apoptosis, resulting in inhibition of the Wnt signaling pathway and suppression of EMT and angiogenesis [183]. Similar studies performed in lung adenocarcinoma A549 cells and small-cell lung cancer suggest that XAV939 attenuates Wnt signaling by reducing c-myc and β-catenin levels, resulting in cell apoptosis [184,185]. Moreover, tankyrase inhibitors further increased apoptosis in combination with 5-fluorouracil/cisplatin, AKT/PI3K inhibitors, by alternation of β-catenin levels, Axin, and CSC markers, overcoming multidrug resistance in colon cancer cells [186,187].…”