Nitric oxide donors reduce the invasion ability of ovarian cancer cells in vitro

Abstract

The most important factors involved in tumor metastasis and angiogenesis are metalloproteinases (MMPs), vascular endothelial growth factor, and multifunctional transforming growth factor β1. These factors are responsible for extracellular matrix degradation, induction of vascular permeability, and enhancement of tumor cells' invasion and metastasis. Elevated expression and secretion of the above-mentioned factors are correlated with the higher aggressiveness of tumors and low patient survival for example, patients with ovarian cancer. Therefore, regulation of the expression, secretion, and activity of these factors is still considered a potent target for therapeutic intervention in cancer patients. Nitric oxide (NO) donors belong to the class of agents with multivalent targeted activities in cancer cells and are considered potential anticancer therapeutics. Our studies have shown that NO donors such as spermine/NO and diethylenetriamine/NO decrease the secretion of vascular endothelial growth factor-A from the OVCAR-3 ovarian cancer cell line, but not from the SK-OV-3 ovarian cancer cell line. The release of MMP-2 from both cell lines was reduced in a soluble guanylate cyclase-dependent manner by spermine/NO and diethylenetriamine/NO. Nevertheless, MMP-2 activity was only affected in SK-OV-3 cells. Both NO donors reduced the transmigration of the ovarian cancer cell lines. We did not observe any significant effect of spermine/NO and diethylenetriamine/NO on mRNA expression of the tested aggressiveness factors. In conclusion, our data indicated that NO donors reduced the metastatic potential of ovarian cancer cells, but its impact is rather low and requires high concentrations of donors. Moreover, both the tested cell lines differed in the susceptibility to NO donors.

The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants

“…Long-term blockade of NO resulted in upregulation of TGF-β and bFGF which led to arteriolar medial thickening and perivascular fibrosis [64]. In a diabetic wound healing model, upregulation of iNOS and ATF3 led to a Ovarian cancer [44] The colon cancer cell line (WiDr) SNP (15.6 mM) A 12-fold increase in MMP-2 mRNA expression following the treatment for 8 h, then declined, with decreased expression of TIMP-1/2, and promoted MMP activity. This improved activity accompanied by cell migration was regulated via cGMPprotein kinase G (PKG)-ERK-1/ 2 dependent mechanism.…”

Nitric oxide and pH modulation in gynaecological cancer

“…However, limited information is available about the functional role of nitric oxide in invasion in gynaecological cancer. It was shown that the nitric oxide donor spermine and diethylenetriamine reduce transmigration of human ovarian cancer cell lines OVCAR3 and SKOV3 and the matrix metalloproteinase 2 activity in SKOV3 cells, thus reducing their metastatic potential .…”

Ovarian cancer: Ca2+-dependent and Ca2+-independent isoforms of NO-synthase functioning in blood lymphocytes of women

“…Рак яєчника (РЯ) -одна з найважчих патологій жіночої репродуктивної системи [1][2][3]. Вивчення патогенезу цього захворювання скеровано на удосконалення методів діагностики та виявлення пухлинного процесу на початковій стадії [2][3][4][5][6].…”

“…Гіперекспресія iNOS виявлена в різних типах злоякісних пухлин. Показано, що селективні інгібітори iNOS гальмують ріст пухлин, розвиток яких індукований дією різних канцерогенів [5,29].…”

“…Здебільшого вважають, що NOS-залежний синтез фізіологічно необхідного NO ("базальний NO") здійснюється за участю еNOS і nNOS, а NOS-залежний синтез додаткових кількостей NO в клітині за розвитку різних патологічних станів реалізується за участю іNOS. Тому активація iNOS є складовою ланкою численних адаптаційно-захистних реакцій клітини й організму [5,6,20,30].…”