@article{5ac6f0ff569843a9a038ea43ae017220,
title = "Diclofenac enhances docosahexaenoic acid-induced apoptosis in vitro in lung cancer cells",
abstract = "Polyunsaturated fatty acids (PUFAs) and non-steroidal anti-inflammatory drugs (NSAIDs) show anticancer activities through diverse molecular mechanisms. However, the anticancer capacities of either PUFAs or NSAIDs alone is limited. We examined whether combining NSAIDs with docosahexaenoic (DHA), commonly derived from fish oils, would possibly synergize their anticancer activity. We determined the viability of lung cancer cell lines (NCI-H1573, A549, NCI-H1299, and NCI-H1975) after exposure to DHA and various NSAIDs. We further conducted cell apoptosis assays and analyzed apoptosis-associated proteins and some key proteins in the RAS/MEK/ERK and PI3K/Akt pathways using western blot analysis. We also determined the impact of the treatment on the expression of inducible cancer-related genes using nCounter PanCancer Pathways gene expression analysis. The results showed that the combination of DHA and NSAIDs increased suppression of cell viability in all the lung cancer cell lines tested compared to each of the compounds used alone, with diclofenac being the most potent NSAID tested. This synergistic effect is especially significant in A549 and NCI-H1573 cells. The combination treatment was more effective at inhibiting clonogenic cell growth and anchorage-independent growth in soft agar, inducing caspase-dependent apoptosis, and altering expression of critical proteins in the RAS/MEK/ERK and PI3K/Akt pathways. The data from this study demonstrate that DHA combined with low dose diclofenac provides greater anticancer potential, which can be further developed for chemoprevention and adjunct therapy in lung cancer.",
keywords = "Cyclooxygenase, Diclofenac, Docosahexaenoic acid, K-Ras, Lung cancer, Nanostring, Non-steroidal anti-inflammatory drugs, Polyunsaturated fatty acids",
author = "Poku, {Rosemary A.} and Jones, {Kylee J.} and {Van Baren}, Megan and Alan, {Jamie K.} and Felix Amissah",
note = "Funding Information: This project was funded by the Ferris State University Faculty Research Grant. Acknowledgments: The authors would like to acknowledge the technical support of Matthew Bernard at MSU flow cytometry core and Meglena L. Kourteva at CMU Bioscience flow cytometry facility for the flow cytometry analysis. Funding Information: Cyclooxygenases are the main enzymes involved in the conversion of polyunsaturated fatty acids (PUFAs) to prostaglandins (PGs) and other eicosanoids [7,8]. Overexpression of Cyclooxygenase-2 (COX-2), a key mediator of inflammation, promotes transformed and invasive phenotypes with increased cell proliferation, motility, invasion, angiogenesis, and resistance to apoptosis [9]. COX-2 remains an important target for colorectal cancers, and more recently, lung cancer therapy and prevention because approximately 70% of lung adenocarcinomas overexpress COX-2 [10]. Targeting COX enzymes for cancer prevention and therapy is supported by several clinical and epidemiological studies [11–13]. Pharmacological inhibition with non-steroidal anti-inflammatory drugs (NSAIDs) or genetic deletion of COX-2 significantly diminishes tumor formation in several cancer models [14–16]. Evidence from recent studies also implicates COX-1 in the chemopreventive roles of NSAIDs [4,6,17–19]. COX-dependent mechanisms involving decreased production of pro-oncogenic PGE2 has been reported as part of the anticancer effects of NSAIDs [8,12,20]. However, several other studies have suggested COX-independent mechanisms for NSAIDs, which involve modulation of NFκB, TGF-β, and Wnt/β-catenin signaling, interference with the Ras-Raf-MEK-ERK signaling cascade, the PI3K/Akt/MAPK signaling axis and/or activation of PPARs [11,21–23]. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = sep,
doi = "10.3390/cancers12092683",
language = "English",
volume = "12",
pages = "1--19",
journal = "Cancers",
issn = "2072-6694",
number = "9",
}