Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling.

Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.

Acute lower limb ischaemia secondary to intestinal occlusion.

In general, acute lower limb ischaemia is caused by embolic, thrombotic or traumatic phenomena. Here, we describe the case of a 67-year-old woman in an emergency room setting who was initially assessed for paralysis and numbness of her lower left limb. On physical examination, the abdomen was distended and non-compressible. An abdominal AngioScan showed complete occlusion of the left iliac artery by extrinsic compression of the dilated small intestine. After a review of the literature, no case was found describing a lower limb ischaemia by extrinsic vascular compression secondary to a compartment syndrome caused by small bowel obstruction. The treatment of this case required surgical decompression of the abdomen which led to an instantaneous reperfusion of the left leg. Unfortunately, the patient deceased a few hours after the surgery due to haemodynamic deterioration.

Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy.

OBJECTIVE: To report survival results in patients with diffuse malignant peritoneal mesothelioma (MPM) treated with maximal cytoreductive surgery followed by immediate intraperitoneal chemotherapy, and to compare them with the median survival of 12-24 months obtained with the standard treatment based on systemic chemotherapy. PATIENTS AND METHODS: Twenty-six patients underwent this new regional approach and a median follow-up of 55 months was achieved after this treatment. Complete cytoreductive surgery (residual disease < 2 mm) was performed in all but one patient. Intraperitoneal chemotherapy was performed with hyperthermia (4245 degrees C) and oxaliplatin in 22 patients. The last 12 patients additionally received irinotecan. Data were prospectively verified and retrospectively analyzed. RESULTS: One patient died postoperatively (4%), and morbidity attained 54%. The median survival exceeded 100 months and the overall 5-year survival rate was 63%. This small series lacks the statistical power required to conduct a well-grounded study on prognostic factors, particularly as the completeness of the surgery is not analyzable here. However, the low-grade histological types had a better disease-free survival rate that was of borderline significance compared to their high-grade counterparts. CONCLUSION: This new approach combining complete cytoreductive surgery considerably increases the survival of patients with MPM compared with the standard treatment based on systemic chemotherapy.

The dietary flavones apigenin and luteolin impair smooth muscle cell migration and VEGF expression through inhibition of PDGFR-beta phosphorylation.

Platelet-derived growth factor (PDGF)-dependent recruitment of mural cells such as pericytes and smooth muscle cells plays a central role in the maturation and stabilization of newly formed vasculature during angiogenesis. In this work, we show that the dietary flavones apigenin and luteolin may interfere with this event through their inhibitory effect on PDGF-dependent phosphorylation of PDGF receptor beta (PDGFR-beta) in smooth muscle cells. Inhibition of PDGFR-beta activity by apigenin and luteolin occurred at low concentrations of the molecules and resulted in the inhibition of extracellular signal-regulated kinase and Akt phosphorylation triggered by PDGF, as well as in a marked reduction of the migratory and invasive properties of these cells. Apigenin and luteolin also strongly inhibit the PDGF-dependent increase in vascular endothelial growth factor (VEGF) mRNA levels and the secretion of VEGF by smooth muscle cells as well as vessel formation in the mouse Matrigel plug assay, suggesting that the inhibitory effects of both molecules on smooth muscle cell function result in impaired angiogenesis. Overall, these results identify apigenin and luteolin as dietary-derived inhibitors of PDGFR-beta activity and suggest that this inhibitory effect may contribute to the chemopreventive properties of these molecules.

Anthocyanidins inhibit migration of glioblastoma cells: structure-activity relationship and involvement of the plasminolytic system.

Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.