Effects of arachidonic acid metabolites in a murine model of squamous cell carcinoma

Abstract

Background A murine model (C3H mice) of squamous cell carcinoma (SCCVII) has been used to investigate the role of arachidonic acid (AA) metabolites in head and neck cancer. Inhibition of tumor growth by cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors of AA metabolism has been associated with changes in levels of AA metabolites in tumor tissues and inflammatory cell infiltrates. To characterize this model further, the effects of exogenous AA metabolites on tumor growth in vitro and in vivo were investigated. Methods Following subcutaneous inoculation with SCCVII tumor cells, control (16 mice) and treatment (24 mice) groups were injected with peritumoral vehicle or AA metabolite. Peritumoral injections of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and 12‐hydroxyeicosatetraenoic acid (12‐HETE) were performed for 16–21 days, and final excised tumor weights were measured. In vitro production of PGE2 and LTB4 was assayed in 2–5 day cultures of SCCVII. Exogenous PGE2 effects on tumor cell growth was assessed with the MTT assay in vitro. Results Tumor growth was significantly inhibited (p = .03) following peritumoral injection of PGE2. Final tumor weights were not affected by LTB4 or 12‐HETE. Tumor inhibition by PGE2 was associated with increased tumor tissue levels of LTB4 (p = .04). In vitro, SCCVII produced minimal amounts of PGE2 and LTB4, and PGE2 had minimal effect on growth. Conclusions In this model, tumor inhibition by exogenous PGE2 is primarily mediated by affecting host‐tumor interactions, although there may be some direct effect on tumor cells. Changes in tumor tissue levels of LTB4 following peritumoral PGE2 administration may be attributable to negative feedback inhibition of the COX pathway with shunting into the LOX pathway. SCCVII cells are probably not a significant source of prostaglandins and leukotrienes in vivo. These data provide insight into the mechanism of action of inhibitors of AA metabolism on tumor growth. © 2000 John Wiley & Sons, Inc. Head Neck 22: 149–155, 2000.

Decreased Risk of Squamous Cell Carcinoma of the Head and Neck in Users of Nonsteroidal Anti-Inflammatory Drugs

“…A study by Tanaka et al [37] involving rats with precancerous lesions of the tongue revealed that the incidence of HNSCC was reduced to 23%–31% with the administration of NSAIDs compared to 71% in rats that did not receive NSAIDs. Laboratory studies have also shown that NSAIDs increase the host immune cell infiltration in tumor cells [38], inhibit the growth of squamous cell cancer in mice [39–41], and cultured human HNSCC cell lines [42]. There has also been immunohistochemical evidence indicating that the expression of COX-2 protein in oral mucosal lesions increases as the lesions progress from hyperplasia to dysplasia with the highest levels of COX-2 stain found in SCC.…”

Effect of Polyunsaturated Fatty Acids and Their Metabolites on Bleomycin-Induced Cytotoxic Action on Human Neuroblastoma Cells In Vitro

“…Studies showed that indeed a combination of PUFAs and conventional anti-cancer drugs have more potent action on tumor cells compared to either compound alone [18] – [23] . Some studies suggested that the tumoricidal action of PUFAs is not dependent on the formation of cyclo-oxygenase (COX) and lipoxygenase (LOX) products though, this has been disputed [1] , [2] , [24] – [28] . This uncertainty of the involvement of COX and LOX products on the growth/apoptosis of tumor cells is further supported by the observation that different prostaglandins either enhance or inhibit growth depending on the dose and type of the compounds tested and much less is known about the action of leukotrienes and thromboxanes on cancer cells [29] – [42] .…”

Eicosanoid metabolism in squamous cell carcinoma cell lines derived from primary and metastatic head and neck cancer and its modulation by celecoxib

“…10 Although, multiple enzymes related to eicosanoid metabolism are similar in terms of structure, substrate preference and mechanisms of action, a variety of biological effects have been demonstrated for their products in various experimental models. [11][12][13][14] In fact, elevated PG levels have been detected in HNSCC cell lines and neoplastic tissues resected from patients. [15][16][17] Furthermore, there is evidence for a strong correlation between PGE 2 synthesis and prognostic significance as well as metastatic ability of tumor cells in vivo, 18,19 Accordingly, COX-2 isoenzyme is frequently upregulated in HN cancers that have been reported to be associated with tumor growth, resistance to apoptosis, metastasis, and angiogenesis.…”