Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells.

AbstractContext: Proton Pump Inhibitors (PPIs) reduce tumor acidity and therefore resistance of tumors to drugs. Carbonic Anhydrase IX (CA IX) inhibitors have proven to be effective against tumors, while tumor acidity might impair their full effectiveness.Objective: To analyze the effect of PPI/CA IX inhibitors combined treatment against human melanoma cells.Methods: The combination of Lansoprazole (LAN) and CA IX inhibitors (FC9-399A and S4) has been investigated in terms of cell proliferation inhibition and cell death in human melanoma cells.Results: The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells.Discussion: These results represent the first successful attempt in combining two different proton exchanger inhibitors.Conclusion: This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alter..

Effect of Modified Alkaline Supplementation on Syngenic Melanoma Growth in CB57/BL Mice.

Tumor extracellular acidity is a hallmark of malignant cancers. Thus, in this study we evaluated the effects of the oral administration of a commercially available water alkalizer (Basenpulver®) (BP) on tumor growth in a syngenic melanoma mouse model. The alkalizer was administered daily by oral gavage starting one week after tumor implantation in CB57/BL mice. Tumors were calipered and their acidity measured by in vivo MRI guided 31P MRS. Furthermore, urine pH was monitored for potential metabolic alkalosis. BP administration significantly reduced melanoma growth in mice; the optimal dose in terms of tolerability and efficacy was 8 g/l (p< 0.05). The in vivo results were supported by in vitro experiments, wherein BP-treated human and murine melanoma cell cultures exhibited a dose-dependent inhibition of tumor cell growth. This investigation provides the first proof of concept that systemic buffering can improve tumor control by itself and that this approach may represent a new strategy in prevention and/or treatment of cancers

Urine alkalization following the administration of single dose of BP.

<p>Effects of BP administration on urine pH (measured with urine strips) at 0, 3 and 24 hours at the BP therapeutic concentrations of 4 and 8 g/l. The urine alkalization reached the zenith at 3 hours and then normalized over time; the peak values were 6.7 ± 0.26 and 7.2 ± 0.15 for the 4 g/l (A) and 8 g/l (B) concentrations respectively. Bars indicate SD. (*) indicate p < 0.05.</p

<i>In vivo</i> tumor growth inhibition induced by BP.

<p>BP shows a dose dependent inhibition of tumor growth in the melanoma B16F10/syngenic mouse model of cutaneous melanoma compared to untreated controls. Tumor inhibition peaked at the BP concentration of 8 g/l, it was less at the concentration of 4 g/l and had a paradoxical decrease at the highest concentration of 16 g/l (p < 0.05). Bars indicate SE. (*) indicate p < 0.05.</p

Comparison of the antiproliferative properties of BP versus Sodium Bicarbonate.

<p><i>In vitro</i> antiproliferative effect of BP in comparison with sodium bicarbonate against murine melanoma B16F10 (A) and human melanoma Mel 501 (B), A375 (C) at 24, 48 and 72 hours, as indicated. The figures show an increased efficacy of the commercial buffer over sodium bicarbonate (p < 0.05) at 8g/l and at all different setting time. Columns are mean percentages of two independent experiments run in triplicate; bars indicate SD. (*) indicate p < 0.05.</p

Tumor alkalization induced by single dose of BP detected by ³¹P MRS.

<p>Effects of BP administration on tumor extracellular pH measured by <i>in vivo</i> ³¹P MRS. Tumors had an average extracellular pH (pHe) of 6.68 ± 0.26 at 24 h before treatment and 7.1 ± 0.1 at 1 hour after treatment (8 g/l). Bars indicate SD. (*) indicate p < 0.05.</p

<i>In vivo</i> 31P MR spectra acquired at different time after BP administration.

<p>A) Axial T1-weighted gradient-echo multislice images from a typical B16F10 tumor 20 days after implant. The light blu rectangles indicate the region of magnetic field optimization. B) <i>In vivo</i> ³¹P spectra acquired at different time after Basenpulver 8 g/L administration: from 40 to 50 minutes (pHe = 7.1), from 50 to 60 minutes (pHe = 7.0) and from 60 to 70 minutes (pHe = 6.9). A small amount of contamination arising from the most acid 3-APP signal (at 34 ppm) and from PCr could be due to CSF and muscle, respectively, because of the close proximity of the implanted tumor to the vertebral column (green arrows). However, the small PCr/α-ATP ratio and the presence of the PME signal ensure the tumor origin of the spectrum. Assignments: 3-APP, 3-amino-propil-phosphonate; PME, phosphomonoesters; Pi, inorganic phosphate; PDE, phosphodiesters; ATP, adenosine triphosphate.</p

Acridine Orange/exosomes increase the delivery and the effectiveness of Acridine Orange in human melanoma cells: A new prototype for theranostics of tumors

Specifically targeted drug delivery systems with low immunogenicity and toxicity are deemed to increase efficacy of cancer chemotherapy. Acridine Orange (AO) is an acidophilic dye with a strong tumoricidal action following excitation with a light source at 466 nm. However, to date the clinical use of AO is limited by the potential side effects elicited by systemic administration. The endogenous nanocarrier exosomes have been recently introduced as a natural delivery system for therapeutic molecules. In this article, we show the outcome of the administration to human melanoma cells of AO charged Exosomes (Exo-AO), in both monolayer and spheroid models. The results showed an extended drug delivery time of Exo-AO to melanoma cells as compared to the free AO, improving the cytotoxicity of AO. This study shows that Exo-AO have a great potential for a real exploitation as a new theranostic approach against tumors based on AO delivered through the exosomes