Antimetastatic activity of a cyclooxygenase-2 inhibitor

Abstract

Cyclooxygenase-2 (COX-2) expression is increased in breast cancer and surgery has been shown to increase the growth of metastatic tumours. We investigated the effect of selective COX-2 inhibition on the growth of metastases in either an experimental metastasis model or following excision of a murine primary breast tumour. 50 000 4T1 mammary carcinoma cells were injected into the mammary fat pad of female BALB/c mice. When the mean TD reached 870.4 mm, tumours were excised and the mice were randomised into two groups (n ¼ 12 per group) to receive daily intraperitoneal injections of the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days. Alternatively, experimental metastases were established by tail-vein injection of 50 000 4T1 cells. Mice received either the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days (n ¼ 12 per group). SC-236 treatment significantly reduced tumour burden, the number and size of spontaneous metastases following primary tumour excision. SC-236 treatment also reduced tumour burden, the number and size of experimental metastases. Immunohistochemical staining demonstrated that COX-2 inhibition reduced microvessel density and increased apoptosis within both spontaneous and experimental metastases. These data clearly demonstrate that the selective COX-2 inhibitor, SC-236, has potent antimetastatic activity against both spontaneous metastases arising following primary tumour excision and experimental metastases.

COX-2 involvement in breast cancer metastasis to bone

“…Although PGE 2 produced by breast cancer cells has a specific role in bone metastasis, our study does not rule out additional roles of COX-2 in cancer progression, which are not specific to bone metastasis. Role of COX-2 in breast cancer has been demonstrated using several different rodent models, including 7,12-dimethyl-benz(a)anthracene-induced mammary carcinogenesis in rat (Harris et al, 2000), MMTV-COX-2 and MMTV-HER2 transgenic mouse models (Liu et al, 2001;Howe et al, 2002;Chang et al, 2004), MMTV-HER2 transgenic/COX-2 knock-out mouse model (Howe et al, 2005) and xenograft mouse models involving inoculation of cancer cells into fat pad (Connolly et al, 2002;Roche-Nagle et al, 2004). These studies indicate an important role of COX-2 in primary tumor growth, angiogenesis and metastasis.…”

Perioperative Use of β-blockers and COX-2 Inhibitors May Improve Immune Competence and Reduce the Risk of Tumor Metastasis

“…Additionally, COX inhibitors were shown to have a preventive effect on the growth of both the primary tumor and metastases via other mechanisms, such as promotion of tumor apoptosis, 3,4,40,41 reduction in the levels of angiogenic agents, 4,[6][7][8] and diminution of tumor microvascular density. 3 Moreover, a recent study reported that two COX inhibitors, indomethacin and celecoxib, downregulated expression levels of MHC-I molecules on murine mammary tumor cells. Decreased expression of MHC-I is a known triggering signal for NK cells to lyse such tumor cells.…”

“…Various tumors have been shown to secrete PGs, 1,2 presumably to escape destruction by suppressing the host's cell-mediated immunity (CMI). Additionally, COX inhibitors were shown to have a preventive effect on the growth of both the primary tumor and metastases via other mechanisms, including the promotion of tumor cell apoptosis, [3][4][5] reduction in the levels of angiogenic agents, [6][7][8] and diminution of tumor microvascular density. 3 As for β-blockers, β1 and β2 adrenoceptors are expressed by several human tumor lines, and catecholamines are potent direct stimulators of migration of various human carcinoma cell types (e.g., colon, breast, and ovary), [9][10][11][12] and of secretion of proangiogenic factors by these tumors (e.g., vascular endothelial growth factor).…”

Promotion of hematogenous metastatic potentials in human KB carcinoma cells with overexpression of cyclooxygenase-2

“…We focused on the role of COX-2 in metastatic potential by using orthotopic inoculation or injection into the left cardiac ventricle of nude mice with KB/COX-2 and KB/ Neo. Orthotopic inoculation of tumor cells in nude mice is well known as a spontaneous metastasis model (19,20). On the other hand, metastasis to liver by injection of tumor cells to portal vein or spleen (21,22) and metastasis to lung by injection of tumor cells to tail vein (20) are also reported as experimental metastasis models.…”

“…Orthotopic inoculation of tumor cells in nude mice is well known as a spontaneous metastasis model (19,20). On the other hand, metastasis to liver by injection of tumor cells to portal vein or spleen (21,22) and metastasis to lung by injection of tumor cells to tail vein (20) are also reported as experimental metastasis models. Although an intra-cardiac injection of tumor cells (23,24) is easier to make metastasis than other models, it is uncommon because of the technical difficulty.…”