Effects of a cyclooxygenase-1-selective inhibitor in a mouse model of ovarian cancer, administered alone or in combination with ibuprofen, a nonselective cyclooxygenase inhibitor

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to be potent inhibitors of the cyclooxygenases. The present study was designed to investigate the effects of a cyclooxygenase (COX)-1 inhibitor, SC-560, administered alone or in combination with ibuprofen on the growth inhibition of s.c. human ovarian SKOV-3 carcinoma and on angiogenesis. The effects of SC-560 and ibuprofen on tumor growth inhibition have been examined in mouse ovarian cancer models. Angiogenesis of both COX inhibitors was measured by reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Prostaglandin E(2) (PGE(2)) levels in tumor tissues of mice were also determined by ELISA. The inhibitory rates in SC-560 group alone and in combination with ibuprofen group were 21.21% and 41.55%, respectively. In combination therapy with SC-560 and ibuprofen, tumor volumes were significantly reduced compared with that of control group (P < 0.05). In treatment groups, both COX inhibitors significantly reduced intratumor PGE(2) levels (all P < 0.01). Microvessel density (MVD) in tumor tissues were significantly decreased from 80.90 +/- 5.14 in vehicle-treated to 40.70 +/- 10.45 and 38.90 +/- 8.41 in SC-560 group alone and combination ibuprofen therapy (all P < 0.01). Ibuprofen was similar to the cyclooxygenase-1-selective inhibitor SC-560 in its ability to suppress the values of MVD of tumor tissues. SC-560 administered alone or in combination with ibuprofen inhibited the COX-associated up-regulation of VEGF. These studies demonstrate synergism between two COX inhibitors and that antiangiogenic therapy can be used to inhibit ovarian cancer growth.

Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: Implications in drug designing and development

“…Similarly, curcumin has been reported to be two folds more potent inhibitor of COX-1 than that of COX-2 (COX-1 IC 50 ¼50 μM, COX-2 IC 50 4100 μM) [1]. Furthermore, in conformity with our in silico results, Li et al [16] has demonstrated inhibition of tumor growth by ibuprofen in a mouse cancer model by preferential inhibition of COX-1. On the other hand, aspirin has been shown to inhibit growth of many types of tumors including breast cancer by preferential inhibition of COX-2 [17].…”

“…Many efforts have been made to find out the possible relevance of COX-1 and COX-2, in relation to various pathophysiological conditions, using specific as well as non-specific drugs and inhibitors. Thus, ibuprofen, a commonly used nonstreroidal anti-inflammatory drug (NSAID), has recently been shown to inhibit tumor growth in a mouse cancer model by preferentially inhibiting COX-1 [16]. On the other hand, aspirin (another NSAID) has been reported to inhibit growth of many types of tumors including breast cancer by preferential inhibition of COX-2 [17].…”

Effect of the combination of a cyclooxygenase-1 selective inhibitor and taxol on proliferation, apoptosis and angiogenesis of ovarian cancer in vivo

“…Our results have shown that SC-560 and taxol therapy inhibited VEGF mRNA expression, and a combination therapy of the two drugs demonstrated a synergistic effect. Previous studies have found that the expression of COX-1 leads to an increased expression of VEGF and that the inhibition of COX-1 reverses this response (15,34,35). The above studies indicate that COX-1 inhibitors may indirectly inhibit VEGF expression by inhibiting COX-1 expression.…”

Cases of psoriasis improved by lowering homocysteine using 4-7 mg folic acid, vitamins B6 and B12 previously worsened using 1-2 mg daily folic acid, B6 and B12 folic acid

“…Since he was 40 years old when he flared and his BMI was low, the risk of having elevated VEGF was high [43] possibly making him a poorer candidate for the effects of a high FA dose. [46][47][48]. Theoretically depending on which type of NOS is preserve these drugs could improve or worsen psoriasis.…”