Inhibition of angiogenesis, tumour growth and metastasis by the NO‐releasing vasodilators, isosorbide mononitrate and dinitrate

Abstract

The effect of the nitric oxide (NO)‐producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice Isosorbide 5‐mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose‐dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of α‐thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside which generates NO non‐enzymatically Mice, implanted intramuscularly with LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a reduction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial cells and to cultures of LLC cells had no effect on their growth characteristics These results indicate that ISMN and ISDN inhibit angiogenesis and tumour growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

“…On the other side, NO-releasing agents have been shown to suppress the metastatic tumor cell behavior in various in vitro and in vivo tumor models by decreasing angiogenesis and, therefore, tumor cell invasion. [9][10][11][12][13] The anti-invasiveness and anti-metastatic properties of NO have been attributed either to inhibition of angiogenic factors such as β-FGF and TGFβ1, [9][10][11] or induction of TIMP-2 production and inhibition of p38. 13 Alternatively, NO has been proposed to interfere with the storeoperated calcium mobilization through regulation of the NO/ cGMP-mediated mechanism, 10 or it can prevent the excessive formation of oxygen radicals and peroxynitrate (ONOO -), which cause cell damage and facilitate tumor metastasis.…”

“…These findings are in agreement with other studies showing the inhibitory effects of NO-releasing agents in metastatic tumor cell behavior both in vitro and in vivo. [9][10][11][12][13] The challenge regarding NO donors as therapeutic agents is to deliver NO in a sustained and controlled manner. NO donors that spontaneously generate large amounts of NO, independent of iNOS induction, are activated at physiological pH.…”

Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

“…Furthermore, one study has shown that inhalant nitrite increased angiogenesis resulting in accelerated tumor growth 102 , while another demon strated that the increased nitrite levels correlated positively with vasculo-and angiogenesis 24 . But the opposite effect was also reported, showing that NO inhibited angiogenesis and tumor growth 69 . These controversial and unclear results 34 , the fact that nitrite is still used in the meat industry 89 and the recently reported presence of nitrite and nitrosamines in many organs including brain, aorta, liver, kidney and the heart 10 suggest that nitrite may not be as dangerous as previously thought and that carefully designed epidemiologic studies of nitrite's biologic role are necessary.…”

Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

“…Additional studies indicated that NO donors reduced tissue angiogenesis and tumour neovascularization (Pipili-Synetos et al, 1995;Sakkoula et al, 1997). However, opinion on the role of NO in angiogenesis has been polarized by disparate observations in the literature.…”