Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background

Abstract

Cyclooxygenase 2 (COX-2) is a key enzyme of the tumorigenesis-inflammation interface and can be induced by hypoxia. A pseudohypoxic transcriptional signature characterizes pheochromocytomas and paragangliomas (PPGLs) of the cluster I, mainly represented by tumors with mutations in von Hippel–Lindau (VHL), endothelial PAS domain-containing protein 1 (EPAS1), or succinate dehydrogenase (SDH) subunit genes. The aim of this study was to investigate a possible association between underlying tumor driver mutations and COX-2 in PPGLs. COX-2 gene expression and immunoreactivity were examined in clinical specimens with documented mutations, as well as in spheroids and allografts derived from mouse pheochromocytoma (MPC) cells. COX-2 in vivo imaging was performed in allograft mice. We observed significantly higher COX-2 expression in cluster I, especially in VHL-mutant PPGLs, however, no specific association between COX-2 mRNA levels and a hypoxia-related transcriptional signature was found. COX-2 immunoreactivity was present in about 60% of clinical specimens as well as in MPC spheroids and allografts. A selective COX-2 tracer specifically accumulated in MPC allografts. This study demonstrates that, although pseudohypoxia is not the major determinant for high COX-2 levels in PPGLs, COX-2 is a relevant molecular target. This potentially allows for employing selective COX-2 inhibitors as targeted chemotherapeutic agents and radiosensitizers. Moreover, available models are suitable for preclinical testing of these treatments.

Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments

“…Additionally, the role of COX-2 in CSC survival and recolonization after therapy has been considered in detail elsewhere, making it clear that inhibiting COX-2 is an effective way to prevent treatment failure due to tumor repopulation [161]. Addressing COX-2 by selective inhibitors or dual drugs as an adjuvant approach is also feasible in NENs [162][163][164][165].…”

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors

“…COX-2 is inducible by cytokines, tumor promotors, and growth factors, whereas constitutive expression is limited to kidneys, brain, the gastro-intestinal tract, and thymus [ 21 , 22 , 23 ]. Often overexpressed in tumors, COX-2 is involved in the regulation of cell proliferation, migration, angiogenesis, apoptosis, metastasis, and immune resistance of tumor cells [ 12 , 13 , 14 , 24 , 25 ]. Different studies reported that the reduction in prostaglandin E2 synthesis in tumors by non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors is associated with chemo-preventive effects in some tumors, such as colon, breast, prostate, lung, head, and neck cancer.…”

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells

“…Cyclooxygenase-2 converts arachidonic acid to prostaglandin H 2 , and by that, produces the key intermediate in the synthesis of prostanoids and thromboxane A 2 [ 8 ]. While COX-2 gene expression is nearly absent in most healthy tissues, it can be induced by pro-inflammatory mediators during acute and chronic inflammatory states as well as in tumor progression and metastasis, exemplified by malignant melanoma [ 9 , 10 ]. In addition, COX-2 is discussed to be responsible for poor response of various types of cancer in radiotherapy [ 11 ].…”

“…COX-2 exists beside its constitutively expressed isoform COX-1, which shares the same reaction specificity but is mainly involved in homeostatic processes and protection of gastric mucosa. In principle, the analgesic, anti-pyretic, and anti-inflammatory action of COX inhibitors that are classified in nonsteroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors (COXIBs) can be attributed to the inhibition of COX-2, while the gastrointestinal toxicity after long-term use especially of NSAIDs results from the concomitant inhibition of COX-1 [ 8 , 9 , 12 , 13 ]. Currently, only selected COXIBs such as celecoxib, etoricoxib, or the prodrug parecoxib are on the market due to an increased risk for cardiovascular incidents such as stroke and heart attacks described after long-term treatment with, e.g., rofecoxib or valdecoxib.…”