TNF-related apoptosis-inducing ligand enhances vinorelbine-induced apoptosis and antitumor activity in a preclinical model of non-small cell lung cancer

Abstract

Abstract. Non-small cell lung cancer (NSCLC) is relatively insensitive to chemotherapy. NP [vinorelbine (NVB) + cisplatin] is the standard chemotherapy regimen in clinical treatment; however, its side-effects are intolerable for most patients. In some reports, the TNF-related apoptosis-inducing ligand (TRAIL) can enhance the sensitivity of chemotherapy drugs by inducing apoptosis without toxicity to normal cells. In the present study, we evaluated the antitumor effects of the two drugs (TRAIL and NVB alone or in combination) by inducing apoptosis in vitro and in vivo. Using the human NSCLC cell line (A549) and a BALB/c nude mice model, we observed the cell viability (MTT assay), cell apoptosis [Hoechst staining, Annexin V/propidium iodide (PI) staining assay, immunohistochemical staining, RT-PCR and western blotting] and cell proliferation (soft agar colony formation and cell cycle assay). The results showed that TRAIL and NVB alone inhibited tumor growth both in vivo and in vitro. However, the combination of the two drugs produced a more potent antitumor effect (P<0.05) and caused more severe apoptosis in tumor tissue (P<0.05). The key molecular protein level of the mitochondrial apoptotic pathway (Bax and caspase-3) was further upregulated by the combination of the two drugs (P<0.01) and either drug alone (P<0.05). The mRNA level of Bcl-2 and Bax in the combination group was downregulated and upregulated respectively, when compared with the control group (P<0.01). The combination group of A549 cells also showed lower viability compared with the one drug alone group (P<0.05). Moreover, the Hoechst staining assay and Annexin V/PI staining assay showed that the combination of the two drugs induced a more potent apoptosis than either drug alone (P<0.05, early apoptosis P<0.01, respectively). In addition, the cell colony numbers were deduced after treatment with TRAIL or NVB alone (P<0.05) and the two drug combination (P<0.01). Cell cycle analysis showed that TRAIL and NVB alone markedly increased the percentage of cells in G1 phase (P<0.05) and the combination of the two drugs decreased the percentage of cells in G2 and S phase (P<0.05). Thus, the combination of TRAIL and NVB can inhibit lung cancer cell growth by affecting the level of key signaling protein expression of the apoptosis pathway.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…Zhu et al combined vinorelbine and TRAIL to treat the A549 cell and BALB/c nude mice model and found that the level of tumor growth inhibition and apoptosis induction was stronger. The combination of the two drugs could further upregulate the expression level of apoptosis-related proteins such as Bax and caspase-3 to inhibit the growth of lung cancer cells [ 339 ]. Fibroblast growth factor 19 (FGF19) is a driver oncogene that is amplified in approximately 14% of HCC patients and overexpressed in 50% of HCC patients, making the FGF19 gene a novel potential target for the treatment of HCC [ 340 , 341 ].…”

“…Studies have shown that brucine, a cytotoxic drug, can exert strong effects in the combined treatment of cancer. When brucine was treated with gemcitabine in MCF-7 breast cancer cells, the results showed that they could synergistically inhibit cancer cell Berberine (Coptidis rhizome) Induce apoptosis Hepatocellular carcinoma [332] Cotylenin A (plant growth regulator) Induce apoptosis and autophagy Multiple myeloma [333] Vinblastine Temsirolimus (mTOR inhibitor) Induce apoptosis Hepatocellular carcinoma [334] Indibulin (Microtubule inhibitor) Induce apoptosis Breast cancer [335] Indirubin (Indigo naturalis) -Cervical cancer [336] Vinorelbine TRAIL (Apoptosis inducer) Induce apoptosis Non-small cell lung cancer [339] FGF401 (FGFR-4 inhibitor) Induce apoptosis Hepatocellular carcinoma [342] Lenvatinib (Tyrosine kinase inhibitor) Induce apoptosis Anaplastic thyroid cancer [343] Schisandrin B (Schisandra chinensis (Turcz.) Baill.…”

RNA-Seq and Network Analysis Revealed Interacting Pathways in TGF-β-Treated Lung Cancer Cell Lines

“…[38][39][40][41] Multiple molecular signaling pathways have been extensively investigated in lung cancer, 12 and the main pathways observed here are believed to be able to provide roadmaps for therapy of this disease, which include: EGFR/Ras/PI3K growth promoting pathways, [42][43][44][45] p53/Rb/P14 ARF growth inhibitory pathways, 46 and Bcl-2/Bax/Fas/FasL apoptotic pathways. 47,48 Our observations in this study further provided valuable clues to understand these pathways in lung cancer cells under the circumstance of TGF transformation. For example, we found that the p53-signaling pathway was upregulated via TGF stimuli in these two cell lines (Table 2).…”

Three new compounds with nitric oxide inhibitory activity from Tirpitzia sinensis, an ethnomedicinal plant from Southwest China

“…The concentrations of compounds that gave 50% inhibiting potential (IC 50 , µM) was calculated by modified Kou type Eq. (2):where X m is the lg of the maximum dose; P is the sum of positive response rate; P m is the largest positive response rate; P n is the smallest positive response rate; I is the lg of the (maximum dose/adjacent dose) [20]. The data analyses were performed with Microsoft Excel 2013.…”