Synergic effect between 5-fluorouracil and celecoxib on hypoxic gastric cancer cells

Abstract

5‑fluorouracil (5‑FU) is commonly used in the treatment of gastric cancer; however, resistance to this drug occurs under hypoxic conditions. Celecoxib may be used to reverse this resistance. The aim of the present study was to elucidate the inhibitory effects and mechanisms of 5‑FU and celecoxib on the gastric cancer cell line SGC7901 under hypoxic conditions. SGC7901 cells were divided into four groups: Hypoxic control group, 5‑FU group, celecoxib group and 5‑FU/celecoxib combination group. Following treatment, the inhibition rates of cells were determined using an MTT assay. Protein and messenger RNA (mRNA) expression of hypoxia‑inducible factor 2α (HIF‑2α), adenosine triphosphate‑binding cassette sub‑family G member 2 (ABCG2) and octamer binding protein 4 (Oct‑4) were determined using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. The results demonstrated that the 5‑FU/celecoxib combination group had a significantly higher inhibition rate than the individually treated 5‑FU and celecoxib groups (P<0.05); inhibition rates were 66.09, 52.61 and 46.1%, respectively. mRNA and protein expression levels of HIF‑2α, ABCG2 and Oct‑4 were significantly lower in the celecoxib and 5‑FU/celecoxib combination groups (P<0.01) compared with those of the hypoxia control and 5‑FU groups. The 5‑FU group demonstrated the highest levels of the respective mRNA and proteins. In conclusion, the results of the present study indicated that celecoxib had anti‑tumor effects, as it was shown to inhibit tumor cell growth via the inhibition of HIF‑2α, ABCG2 and Oct‑4. The 5‑FU/celecoxib combination had a synergic effect on tumor growth inhibition. This therefore suggested that inhibition of HIF‑2α, ABCG2 and Oct‑4 may be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment.

Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment

“…In keeping with previous reports [20, 52, 53], we observed that development of resistance to 5FU treatment is typically associated with the detection of ischemic areas within MCTS, whereas progress toward the development of necrotic areas within MTCS appears to associate with increasing resistance to treatment only at the highest dose tested. Accordingly, sensitivity to 5FU is associated to the presence of high percentages of Ki-67 proliferating cells in “early” stage MCTS.…”

NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future

“…199 Furthermore, this combination showed a synergistic effect on gastric tumor growth inhibition by decreasing the mRNA and protein expression levels of hypoxia-inducible factor 2α, adenosine triphosphate-binding cassette subfamily G member 2, and octamer binding protein 4. 200,201 Additionally, the topical treatment with this combination was up to 70% more effective in reducing the number of UVB-induced skin tumors than 5-fluorouracil treatment alone. Thus, several phase I and II trials were designed and carried out on patients with hepatocellular carcinoma, 202 metastatic colorectal cancer, 203,204 or advanced esophageal 205 cancer.…”

“…Several clinical and preclinical studies on the combinatory treatment of NSAIDs and chemotherapeutic agents have demonstrated synergistic antitumoral activity on different types of cancer, whether they are administrated alongside EGCG, , statins, − curcumin, − metformin, − or DFMO. ,− Numerous studies have also demonstrated the enhancement in the antitumoral activity of different well-known chemotherapeutic drugs when administrated in combination with NSAIDs. These studies are outlined in Tables and , including cisplatin, − sorafenib, − doxorubicin, − 5-fluorouracil, − …”