Diclofenac Sensitizes Signet Ring Cell Gastric Carcinoma Cells to Cisplatin by Activating Autophagy and Inhibition of Survival Signal Pathways

Abstract

Gastric cancer has one of the highest incidence rates of cancer worldwide while also contributing to increased drug resistance among patients in clinical practice. Herein, we have investigated the role of diclofenac (DCF) on sensitizing cisplatin resistance in signet ring cell gastric carcinoma cells (SRCGC). Non-toxic concentrations of DCF significantly augmented cisplatin-induced cell death in cisplatin-resistant SRCGC cells (KATO/DDP) but not in cisplatin-sensitive SRCGC cells (KATOIII). Consistently, concomitant treatment of DCF and cisplatin significantly enhanced autophagic cell death due to overproduction of intracellular reactive oxygen species (ROS). At the molecular level, the induction of ROS has been associated with a reduction in antioxidant enzymes expression while inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Moreover, the combination of DCF and cisplatin also inhibited the expression of survival proteins including Bcl-2, Bcl-xL, cIAP1 and cyclin D1 in KATO/DDP cells when compared with cisplatin alone. This was due, at least in part, to reduce MAPKs, Akt, NF-κB, AP-1 and STAT-3 activation. Taken together, our results suggested that DCF potentiated the anticancer effect of cisplatin in SRCGC via the regeneration of intracellular ROS, which in turn promoted cell death as an autophagy mechanism and potentially modulated the cell survival signal transduction pathway.

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells

“…Some well-known NSAIDs are already being repurposed: they can be used not only in the treatment of cancer-related pain but also as anticancer drugs and chemosensitizing drugs [ 24 , 41 , 51 ]. The cytotoxic action of NSAIDs is realized via different mechanisms: a decrease in the expression of MYC (a family of regulator genes and protooncogenes that code for transcription factors), the regeneration of intracellular ROS and induction of apoptotic death, cell cycle arrest at different checkpoints, the inhibition of cell proliferation and migration, activating autophagy, and microtubule destabilization [ 29 , 52 ]. DCF also sensitizes cancerous cells to cisplatin and 5-fluorouracil [ 41 , 52 ].…”

“…The cytotoxic action of NSAIDs is realized via different mechanisms: a decrease in the expression of MYC (a family of regulator genes and protooncogenes that code for transcription factors), the regeneration of intracellular ROS and induction of apoptotic death, cell cycle arrest at different checkpoints, the inhibition of cell proliferation and migration, activating autophagy, and microtubule destabilization [ 29 , 52 ]. DCF also sensitizes cancerous cells to cisplatin and 5-fluorouracil [ 41 , 52 ]. The chemosensitizing activity of NSAIDs is due to the inhibition of both the expression and enzyme activity of SOD2 and COX-2.…”

New Advancements in Cisplatin-Based Treatments

“…It has been shown that diclofenac, a nonsteroidal anti-inflammatory drug, enhances cisplatin cytotoxicity in signet ring cell gastric carcinoma cells. The use of diclofenac in combination therapy with cisplatin significantly increases ROS-induced macroautophagy [ 10 ]. Aiming to improve the cancer pharmacological approach, a pilot study demonstrated, in a neuroblastoma xenograft model, the strengthening of cisplatin effects when administered as cocktail therapy with acetazolamide, a carbonic anhydrase isoform IX inhibitor, and fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells [ 11 ].…”