Antiangiogenic activity of aplidine, a new agent of marine origin

Abstract

The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF-and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

“…In vitro and in vivo, Aplidin inhibited the neovascularisation associated with MM disease. These results support the earlier hypothesis proposed by others that Aplidin exerts a potent antiangiogenic activity by having a direct effect on endothelial cells, in addition to inhibiting production of angiogenic factors (Taraboletti et al, 2004). As seen in this study, Aplidin inhibited, in our experiments, both the physiological as the 5T33MMvv-conditioned media-induced angiogenesis seen in a rat aortic ring assay.…”

“…The elucidation of direct effect against the VEGF loop has also been studied in several preclinical in vitro and in vivo models (Taraboletti et al, 2004). The results of these studies show that Aplidin reduces secretion of VEGF from MOLT-4 human leukaemia cells in vitro and has been shown to reduce the expression of VEGFR-1 in the same cell line Biscardi et al, 2005).…”

Aplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation

“…12 In line with this, Aplidin s is anti-angiogenic by inhibiting VEGF-and fibroblast growth factor-2-induced endothelial cell functions (proliferation, migration, invasiveness). 13 However, Aplidin s inhibited VEGF secretion only in one out of four lines derived from patients with acute lymphoblastic leukaemia, and this effect was unrelated to its cytotoxicity. 14 In conditions of maximal growth stimulation in vitro no differences in drug sensitivity have been observed between normal and tumoral cells.…”

Anti-angiogenic action of plasma hyaluronan binding protein in human umbilical vein endothelial cells

“…The process of angiogenesis requires endothelial cell proliferation, extracellular matrix degradation and invasion through the underlying basement membrane and interstitial matrix and, finally, spatial organization to form a network of new vessels (24). Therefore, we investigated whether PHBP could affect endothelial cell functions relevant to angiogenesis in vitro.…”