Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

Abstract

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet͞serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib-or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti-and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro-and antiangiogenic growth factors.nitric oxide ͉ angiogenesis ͉ nonsteroidal antiinflammatory drug ͉ endothelium ͉ growth factors

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

“…23,24 This is particularly so at the margin of gastric ulcers (both in humans and in rodent models), 25,26 and contributes significantly to healing. 27,28 In the present study, we observed that male Muc-2-deficient mice had significantly reduced up-regulation of COX-2, compared with female . Expression of Muc-2 and Muc-5ac in mice with gastric ulcers induced by serosal application of acetic acid (10 days before harvesting of tissue).…”

Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

“…Importantly, consistent with the known ability of COX-2 inhibitors to interfere with neoangiogenesis (4,41), in our series, celecoxib treatment was associated with the shifting of the balance between circulating levels of VEGF and endostatin toward an ''antiangiogenetic'' state, as also reported in a preclinical model of gastric ulcer healing (42). In conclusion, we reported the first evidence in humans that celecoxib, besides the direct effects on tumor proliferative potential and neoangiogenesis, restores~expression by TIL in primary cervical tumors, suggesting that a positive modulation of immune function may serve as an additional mechanism supporting the antitumor effect of this class of drugs.…”

COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma

“…10,11,13,14 Its role is mediated by a number of molecules such as VEGF-A, CD44 and matrix metalloproteinases, 15 and results in the induction of tumor angiogenesis, increased invasiveness, apoptosis and immune surveillance inhibition and increased cell proliferation. Also, increased COX-2 expression was associated with poor prognosis in a number of malignancies, [16][17][18] and head and neck squamous cell carcinoma, although the small number of patients enrolled in the studies for head and neck squamous cell carcinoma does not permit the extraction of valid conclusions. 10,11,13,14 VEGF-C is a member of the VEGF family and along with VEGF-D is considered to be responsible for tumor lymphangiogenesis and lymph node metastases.…”