Celecoxib in Cancer Therapy and Prevention – Review

Tołoczko-Iwaniuk, Natalia; Dziemiańczyk-Pakieła, Dorota; Nowaszewska, Beata Klaudia; Celińska-Janowicz, Katarzyna; Miltyk, Wojciech

doi:10.2174/1389450119666180803121737

Cited by 124 publications

(96 citation statements)

References 115 publications

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“…Various mechanisms of the anticancer potential of celecoxib have been indicated in the available literature. Many authors suggest that it is not only the inhibition of COX-2 but the regulation of other factors involved in the development of malignant tumours by the drug that has a considerable impact on hindering tumour growth (i.e., a decrease in OCT4, SOX2, and BMP7 gene expression, increase in the expression of E-cadherin gene, Wnt/β-catenin, cell adhesion molecules, and surface receptors: AMFR and EGFR, induction of p53 gene expression) [39]. However, no evidence of the drug's effect on PRODH/POX activity has been demonstrated to date.…”

Section: Discussionmentioning

confidence: 99%

Proline-Dependent Induction of Apoptosis in Oral Squamous Cell Carcinoma (OSCC)—The Effect of Celecoxib

Tołoczko-Iwaniuk

Dziemiańczyk-Pakieła

Celińska-Janowicz

et al. 2020

Cancers

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Background: Oral squamous cell carcinoma remains a significant worldwide public health challenge, associated with high morbidity and mortality. Treatment of this type of cancer lacks effective medication. Moreover, there are very few specific biomarkers that are useful in early diagnosis or treatment optimisation. Proline metabolism may prove to be of importance in the search for new treatment modalities. Methods: To evaluate the significance of proline metabolism in the development of oral cancer, proline concentration was assessed in oral cancer tissue and normal oral mucosa. The results were compared to the clinical stage and histological grade of the tumours. Moreover, the expression of proteins involved in proline metabolism via proline dehydrogenase/oxidase (PRODH/POX, PPARγ, HIF1-α) was determined. In the next stage of the study, conducted on cell lines of tongue cancer treated with celecoxib, the aforementioned factors involved in proline metabolism were evaluated. Cellular viability and cell proliferation, as well as apoptosis, were also assessed. Results: Our research results indicate that a high intracellular proline concentration and expression of factors involved in its metabolism correlate with the clinical stage and histological grade of oral cancer. Moreover, we are the first researchers to demonstrate that celecoxib can affect proline metabolism, causing an increase in pro-apoptotic factors (PRODH/POX, PPARγ), reducing the expression of HIF-1α and activating apoptosis. Conclusions: Proline metabolism, due to its involvement in the process of apoptosis, can be of great importance in anticancer therapy. It appears that celecoxib, which influences the PRODH/POX pathway, may be a promising therapeutic compound in oral cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Proline-Dependent Induction of Apoptosis in Oral Squamous Cell Carcinoma (OSCC)—The Effect of Celecoxib

Tołoczko-Iwaniuk

Dziemiańczyk-Pakieła

Celińska-Janowicz

et al. 2020

Cancers

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“…Moreover, another group revealed that COX inhibitors could effectively upregulate the production of CXCL9 in ovarian and breast cancers since PGE 2 , a downstream product of COX, negatively regulates CXCL9 expression . Focusing on COX inhibitors should be appealing because it has been well recognized as a useful candidate for repositioning drugs in treating and preventing cancers . Furthermore, overexpression of COX, especially COX‐2 isoform, is deemed oncogenic; it has contributed to immune evasion in many types of cancer .…”

Section: Discussionmentioning

confidence: 99%

Endogenous CXCL9 affects prognosis by regulating tumor‐infiltrating natural killer cells in intrahepatic cholangiocarcinoma

et al. 2020

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CXCL9, an IFN-γ inducible chemokine, has been reported to play versatile roles in tumor-host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor-infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor-infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor-related apoptosis-inducing ligand-expressing NK cells into tumors, CXCL9-sufficient cells were less tumorigenic in the liver than CXCL9-deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9-expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9-expressing iCCA by augmenting anti-tumor immune surveillance. K E Y W O R D S CXCL9, intrahepatic cholangiocarcinoma, natural killer cell, tumor necrosis factor-related apoptosis-inducing ligand, tumor-infiltrating lymphocyte S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Fukuda Y, Asaoka T, Eguchi H, et al. Endogenous CXCL9 affects prognosis by regulating tumorinfiltrating natural killer cells in intrahepatic cholangiocarcinoma. Cancer Sci. 2020;111:323-333. https ://

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“…The COX2 selective inhibitor celecoxib alone and in combination with BRAF/MEKi has shown tumor inhibitory effects in preclinical melanoma studies [ 44 , 45 ]. Clinical trials have also reported the effect of COX2 inhibitors, alone or combined with other treatment modalities, in cancer patients [ 17 , 18 ]. However, there are no clinical reports investigating the treatment effect of COX2 inhibitors on BRAF/MEKi melanoma resistance.…”

Section: Discussionmentioning

confidence: 99%

“…While COX1 is constitutively expressed, COX2 is induced by different factors, such as growth factors and proinflammatory cytokines, including CCL2. Celecoxib is a nonsteroidal anti-inflammatory drug that specifically inhibits COX2, commonly used for the treatment of rheumatoid arthritis [ 18 ]. This drug is currently being repurposed in a clinical trial evaluating its treatment and prevention of cancer [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

et al. 2020

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Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Graphical Abstract

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Celecoxib in Cancer Therapy and Prevention – Review

Cited by 124 publications

References 115 publications

Proline-Dependent Induction of Apoptosis in Oral Squamous Cell Carcinoma (OSCC)—The Effect of Celecoxib

Proline-Dependent Induction of Apoptosis in Oral Squamous Cell Carcinoma (OSCC)—The Effect of Celecoxib

Endogenous CXCL9 affects prognosis by regulating tumor‐infiltrating natural killer cells in intrahepatic cholangiocarcinoma

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

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