Abstract
Background: Aspirin has recently emerged as an anticancer drug, but its therapeutic effect on lung cancer has been rarely reported, and the mechanism of action is still unclear. Long-term use of celecoxib in large doses causes serious side effects, and it is necessary to explore better ways to achieve curative effects. In this study, we evaluated the synergistic anticancer effects of celecoxib and aspirin in non-small cell lung cancer (NSCLC) cells. Methods: In vitro, we evaluated the combined effects of celecoxib (40 μM) and aspirin (8 mM) on cell apoptosis, cell cycle distribution, cell proliferation, cell migration and signaling pathways. Furthermore, the effect of aspirin (100 mg/kg body weight) and celecoxib (50 mg/kg body weight) on the growth of xenograft tumors was explored in vivo. Results: Our data suggest that cancer sensitivity to combined therapy using low concentrations of celecoxib and aspirin was higher than that of celecoxib or aspirin alone. Further research showed that the anti-tumor effect of celecoxib combined with aspirin was mainly produced by activating caspase-9/caspase-3, arresting cell cycle and inhibiting the ERK-MAPK signaling pathway. In addition, celecoxib alone or in combination with aspirin inhibited the migration and invasion of NSCLC cells by inhibiting MMP-9 and MMP-2 activity levels. Moreover, we identified GRP78 as a target protein of aspirin in NSCLC cells. Aspirin induced an endoplasmic reticulum stress response by inhibiting GRP78 activity. Furthermore, combination therapy also exhibited a better inhibitory effect on tumor growth in vivo. Conclusions: Our study provides a rationale for further detailed preclinical and potential clinical studies of the combination of celecoxib and aspirin for NSCLC therapy.
| Original language | English (US) |
|---|---|
| Journal | Therapeutic Advances in Medical Oncology |
| Volume | 12 |
| DOIs | |
| State | Published - 2020 |
Funding
Aspirin (purity ⩾99.0%), celecoxib (purity ⩾99.0%), universal tissue fixative, dimethyl sulfoxide (DMSO), streptavidin beads, urea, Tris(2-carboxyethyl)phosphine (TCEP), phosphoric acid and Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) were purchased from Sigma-Aldrich (St. Louis, USA). Cell culture flask and dish were purchased from NUNC (Denmark). Transwell chamber was purchased from Corning (New York, USA). Cell Counting Kit-8 (C0039), EdU cell proliferation assay kit (C0071S), One Step TUNEL Apoptosis Assay Kit (C1086) were purchased from Beyotime Biotechnology (Shanghai, China). BCA Protein Assay Kit (CW0014S) was purchased from CoWin Biosciences (Beijing, China). Biotin-azide was purchased from Click Chemistry Tools (Scottsdale, AZ, USA). Unless otherwise stated, all the other reagents used in biochemical methods were purchased from Sigma-Aldrich (St. Louis, USA). Aspirin probes (Asp-P1 and Asp-P2) were kindly supported by Dr. Jigang Wang from National University of Singapore (West Coast, Singapore). Lipo2000 was purchased from Life Technologies (Carlsbad, CA, USA). Opti-MEM was purchased from Gibco Life Technologies (Grand Island, NY, USA). Reverse transcription kit was purchased from TOYOBO (Kita-ku, Osaka, Japan). Interfering fragment was purchased from GenePharma (Shanghai, China). The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was supported by grants from the Chinese National Natural Sciences Foundation (81773099 and 81630092) and the National Key R&D Program of China (2017YFA0506000). The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was supported by grants from the Chinese National Natural Sciences Foundation (81773099 and 81630092) and the National Key R&D Program of China (2017YFA0506000).
Keywords
- GRP78
- NSCLC
- apoptosis
- aspirin
- celecoxib
- cell cycle arrest
ASJC Scopus subject areas
- Oncology
