COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer

Gulyás, Miklós; Mattsson, Johanna Sofia Margareta; Lindgren, Andrea; Ek, Lars; Lundström, Kristina Lamberg; Behndig, Annelie F.; Holmberg, Erik; Micke, Patrick; Bergman, Bengt

doi:10.1080/0284186x.2017.1400685

Cited by 22 publications

(13 citation statements)

References 26 publications

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“…Both celecoxib and pantoprazole are FDA-approved common drugs. Celecoxib, as a nonsteroidal anti-inflammatory drug, was reported to be used in the treatment of NSCLC due to the relationship between cancer and inflammation 31 . Moreover, pantoprazole was considered to increase the sensitivity of drug-resistant cancer cells such as lymphomas and gastric adenocarcinomas 32 .…”

Section: Discussionmentioning

confidence: 99%

Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

et al. 2019

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MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA2 signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.

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Section: Discussionmentioning

confidence: 99%

Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

et al. 2019

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“…It prevents metastatic progression, which provides additional support for the role of COX-2 in EMT induction. Conversely, some clinical trials have shown that the COX-2 inhibitor, celecoxib, is effective at controlling tumor progression [156,157]. This discrepancy may be due to the differences between these two inhibitors and their underlying molecular mechanisms.…”

Section: Clinical Significance Of Metabolic Regulation In Cancer Tmentioning

confidence: 99%

Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

Kang

Kim

Lee

et al. 2019

IJMS

119

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Activation of epithelial–mesenchymal transition (EMT) is thought to be an essential step for cancer metastasis. Tumor cells undergo EMT in response to a diverse range of extra- and intracellular stimulants. Recently, it was reported that metabolic shifts control EMT progression and induce tumor aggressiveness. In this review, we summarize the involvement of altered glucose, lipid, and amino acid metabolic enzyme expression and the underlying molecular mechanisms in EMT induction in tumor cells. Moreover, we propose that metabolic regulation through gene-specific or pharmacological inhibition may suppress EMT and this treatment strategy may be applied to prevent tumor progression and improve anti-tumor therapeutic efficacy. This review presents evidence for the importance of metabolic changes in tumor progression and emphasizes the need for further studies to better understand tumor metabolism.

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“…These inconsistent results and the fact that COX-2 expression in tumor or stromal cells has no impact on the effect of celecoxib ( 39 , 41 ) may be explained by the various expression patterns of the downstream PGE2 receptors, which vary between organs and cell lines ( 42 ). Multiple HNSCC cell lines have been reported with wide variation of EP expression patterns ( 14 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase‑2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma

et al. 2021

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Cyclooxygenase-2 (COX-2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is associated with the progression in various types of cancer, and its expression has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX-2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX-2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX-2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resection with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX-2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX-2 expression with stemness property, the expression levels of CSC-associated genes after exposure to celecoxib were assessed by reverse transcription-quantitative PCR. A sphere formation assay was also performed using ultra-low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX-2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX-2 inhibition led to downregulation of CSC-associated gene expression and sphere formation. The present findings suggested that COX-2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX-2 may enhance chemo-sensitivity in HNSCC. Therefore, COX-2 may be an attractive target for the treatment of HNSCC.

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COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer

Abstract: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.

Cited by 22 publications

References 26 publications

Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

Cyclooxygenase‑2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma

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