Docking scores (kcal/mol) of GABA, ALA and MAL.

<p>Docking scores (kcal/mol) of GABA, ALA and MAL.</p

Journal of Biomedical Optics / Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy : the influence of light color and irradiance on the treatment outcome in vitro

Hexyl 5-aminolevulinate (HAL) is a lipophilic derivative of 5-aminolevulinate, a key intermediate in biosynthesis of the photosensitizer protoporphyrin IX (PpIX). The photodynamic efficacy and cell death mode after red versus blue light illumination of HAL-induced PpIX have been examined and compared using five different cancer cell lines. LED arrays emitting at 410 and 624 nm served as homogenous and adjustable light sources. Our results show that the response after HAL-PDT is cell line specific, both regarding the shape of the dose-survival curve, the overall dose required for efficient cell killing, and the relative amount of apoptosis. The ratio between 410 and 624 nm in absorption coefficient correlates well with the difference in cell killing at the same wavelengths. In general, the PDT efficacy was several folds higher for blue light as compared with red light, as expected. However, HAL-PDT624 induced more apoptosis than HAL-PDT410 and illumination with low irradiance resulted in more apoptosis than high irradiance at the same lethal dose. This indicates differences in death modes after low and high irradiance after similar total light doses. From a treatment perspective, these differences may be important.(VLID)481032

GABA (a), ALA (b) and MAL (c) ESPs.

<p><b>Color coding of ESPs as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065200#pone-0065200-g004" target="_blank"><b>Figure 4</b></a><b>.</b></b></p

Central substrate binding site.

<p>Amino acids detected by ICM PocketFinder in the outward-occluded GAT models; in <i>italics</i>: amino acids not detected in the respective models.</p

Enhanced Efficacy of Bleomycin in Bladder Cancer Cells by Photochemical Internalization

Bleomycin is a cytotoxic chemotherapeutic agent widely used in cancer treatment. However, its efficacy in different cancers is low, possibly due to limited cellular internalization. In this study, a novel approach known as photochemical internalization (PCI) was explored to enhance bleomycin delivery in bladder cancer cells (human T24 and rat AY-27), as bladder cancer is a potential indication for use of PCI with bleomycin. The PCI technique was mediated by the amphiphilic photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) and blue light (435 nm). Two additional strategies were explored to further enhance the cytotoxicity of bleomycin; a novel peptide drug ATX-101 which is known to impair DNA damage responses, and the protease inhibitor E-64 which may reduce bleomycin degradation by inhibition of bleomycin hydrolase. Our results demonstrate that the PCI technique enhances the bleomycin effect under appropriate conditions, and importantly we show that PCI-bleomycin treatment leads to increased levels of DNA damage supporting that the observed effect is due to increased bleomycin uptake. Impairing the DNA damage responses by ATX-101 further enhances the efficacy of the PCI-bleomycin treatment, while inhibiting the bleomycin hydrolase does not.<p>Copyright © 2014 Yan Baglo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p

Enhanced Efficacy of Bleomycin in Bladder Cancer Cells by Photochemical Internalization

Bleomycin is a cytotoxic chemotherapeutic agent widely used in cancer treatment. However, its efficacy in different cancers is low, possibly due to limited cellular internalization. In this study, a novel approach known as photochemical internalization (PCI) was explored to enhance bleomycin delivery in bladder cancer cells (human T24 and rat AY-27), as bladder cancer is a potential indication for use of PCI with bleomycin. The PCI technique was mediated by the amphiphilic photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) and blue light (435 nm). Two additional strategies were explored to further enhance the cytotoxicity of bleomycin; a novel peptide drug ATX-101 which is known to impair DNA damage responses, and the protease inhibitor E-64 which may reduce bleomycin degradation by inhibition of bleomycin hydrolase. Our results demonstrate that the PCI technique enhances the bleomycin effect under appropriate conditions, and importantly we show that PCI-bleomycin treatment leads to increased levels of DNA damage supporting that the observed effect is due to increased bleomycin uptake. Impairing the DNA damage responses by ATX-101 further enhances the efficacy of the PCI-bleomycin treatment, while inhibiting the bleomycin hydrolase does not

Entry pathway ESPs.

<p>ESPs of the entry pathways detected in the outward-open GAT models (grey ribbon representation). a) GAT-1, b) GAT-2, c) GAT-3, and d) BGT-1. Blue spheres: Na1 and Na2 sodium ions. Color coding: red: negative ESP; blue: positive ESP; grey: neutral ESP.</p

Outward-occluded GAT-2 model.

<p>Membrane view of the outward-occluded GAT-2 homology model (grey ribbon representation). Orange wire: the putative substrate binding site detected by ICM PocketFinder; blue spheres: Na1 and Na2 sodium ions; green sphere: chloride ion; dotted line: missing EL2 residues.</p

GAT-1 exit pathway ESPs.

<p>GAT-1 in grey ribbon representation. Color coding of ESPs as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065200#pone-0065200-g004" target="_blank">Figure 4</a>.</p