Perillyl Alcohol Is an Angiogenesis Inhibitor

Department of Pharmacy, University of Patras, Rhion, West Greece, Greece
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2004; 311(2):568-75. DOI: 10.1124/jpet.104.070516
Source: PubMed


Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Thus, antiangiogenic therapy is one of the most promising approaches to control cancer. In the present work, we examined the ability of perillyl alcohol (POH), a dietary monoterpene with well-established tumor chemopreventive and chemotherapeutic activity, to interfere with the process of angiogenesis. POH remarkably prevented new blood vessel growth in the in vivo chicken embryo chorioallantoic membrane assay and proved to be effective in inhibiting the morphogenic differentiation of cultured endothelial cells into capillary-like networks both in collagen gel and Matrigel models. In addition, POH reduced the cell number in a proliferation assay and induced apoptosis of endothelial cells as indicated by the POH-mediated increase of caspase-3 activity and DNA fragmentation. Consistent with the observed antisurvival effect, POH treatment resulted in a significant inhibition of Akt phosphorylation in endothelial cells. Finally, POH was able to differentially modulate the release of two important angiogenic regulators: vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2). POH decreased the release of VEGF from cancer cells but stimulated the expression of Ang2 by endothelial cells, indicating that it might suppress neovascularization and induce vessel regression. Overall, these data underscore the antiangiogenic potential of POH and suggest that POH, in addition to its anticancer activity, may be an effective agent in the treatment of angiogenesis-dependent diseases.

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    • "High levels of angiogenic factor EGF correlates with large volume of tumor and also with the degree of malignancy especially among astrocytoma patients (Kanno et al. 1993; Nguyen 1997). Loutrari et al. (2004) using in vitro experiments showed that POH decreased the production of VEGF and Ang 2, an indication that POH has an anti-angiogenic effect. Yet, there is no available data concerning POH effect upon angiogenic cytokine EGF production. "
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    ABSTRACT: Malignant gliomas are associated with alteration in EGF/EGFR signaling. Functional EGF+61A>G polymorphism is implicated with risk, recurrence, and progression of glioma. This study aimed to establish a putative association of EGF+61A>G with risk of glioma development, production of angiogenic growth factor EGF, and the response to perillyl alcohol administered by intranasal route. The study included 83 patients with recurrent glioma enrolled in Phase I/II trial for intranasal perillyl alcohol therapy and subjects without cancer (n = 196) as control group. DNA was extracted from blood samples, EGF genotype performed with PCR-RFLP assay, and EGF circulating levels by enzyme immunoassay. Adequate statistical tests were performed to verify associations between polymorphism and glioma risk, and genotype correlation with EGF circulating levels. The log-rank test was also used to evaluate differences on patient survival. Patients with primary glioblastoma had high frequency of AA genotype (p = 0.037) and A allele (p = 0.037). Increased EGF circulating levels were observed in glioma patients with AA (p = 0.042), AG (p = 0.006), and AA + AG (p = 0.008) genotypes compared with GG. Patients with GG genotype showed increased but not significant (p > 0.05) survival rate, and EGF levels lower than 250 pg/mL was consistently (p = 0.0374) associated with increased survival. Presence of EGF+61A>G polymorphism in Brazilian subjects was associated with glioma risk and increased circulating EGF levels. Better response to perillyl alcohol-based therapy was observed in a group of adult Brazilian subjects with lower EGF levels.
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    • "To asses neo-vessel formation in tumor microenvironment, we used the CAM of the chick embryo model in a modified version that combined two previously described protocols [16,36]. Briefly, 5 × 105 tumor cells that had been pre-treated for 2 h with mastic oil (0.01–0.04% v/v, POH (0.5–1 mM) or vehicle (0.05% DMSO), were applied on the exposed upper part of the membrane on day 9 of embryo development, onto an area of 1 cm2 restricted by a plastic ring. "
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    ABSTRACT: Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01-0.04% v/v): (a) abrogated their Matrigel invasion and migration capabilities in transwell assays; (b) reduced the levels of secreted MMP-2; (c) restricted phorbol ester-induced actin remodeling and (d) limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis.
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    • "Some of the compounds identified as substrates were oxidized with moderate efficiency to organic products, but others primarily triggered uncoupled turnover. In terms of monoterpene compounds other than camphor, an Escherichia coli whole-cell biocatalyst transformed with a tricistronic construct of P450cam, Pd and PdR was reported to oxidize limonene to perillyl alcohol [55], a potential anti-cancer compound being researched in phase I and phase II clinical trials [56] [57]. "
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