Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.

Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target.

Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.

EMF radiation at 2450 MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus.

AIMS: Electromagnetic fields (EMFs) can act as inducers or mediators of stress response through the production of heat shock proteins (HSPs) that modulate immune response and thymus functions. In this study, we analyzed cellular stress levels in rat thymus after exposure of the rats to a 2.45 GHz radio frequency (RF) using an experimental diathermic model in a Gigahertz Transverse Electromagnetic (GTEM) chamber. MAIN METHODS: In this experiment, we used H&E staining, the ELISA test and immunohistochemistry to examine Hsp70 and Hsp90 expression in the thymus and glucocorticoid receptors (GR) of 64 female Sprague­Dawley rats exposed individually to 2.45 GHz (at 0, 1.5, 3.0 or 12.0 W power). The 1 g averaged peak and mean SAR values in the thymus and whole body of each rat to ensure that sub-thermal levels of radiation were being reached. KEY FINDINGS: The thymus tissue presented several morphological changes, including increased distribution of blood vessels along with the appearance of red blood cells and hemorrhagic reticuloepithelial cells. Levels of Hsp90 decreased in the thymus when animals were exposed to the highest power level (12 W), but only one group did not show recovery after 24 h. Hsp70 presented no significant modifications in any of the groups. The glucocorticoid receptors presented greater immunomarking on the thymic cortex in exposed animals. SIGNIFICANCE: Our results indicate that non-ionizing sub-thermal radiation causes changes in the endothelial permeability and vascularization of the thymus, and is a tissue-modulating agent for Hsp90 and GR.

Contribution of the immune system to bystander and non-targeted effects of ionizing radiation.

Considerable progress has recently been achieved in the understanding of molecular mechanisms involved in cellular radiation responses and radiation mediated microenvironmental communication. In line with that, it has become more and more obvious that X-irradiation causes distinct immunological effects ranging from anti-inflammatory activities if applied at low (<1 Gy) doses to harmful inflammatory side effects, radiation-induced immune modulation or induction of anti-tumour immune responses at higher doses. Moreover, experimental and clinical evidences indicate that these effects not only originate from direct nuclear damage but also include non-(DNA) targeted mechanisms including bystander, out of field distant bystander (abscopal) effects and genomic instability. The purpose of the present review is to elucidate immune responses that are initiated or affected by ionizing radiation, with a special emphasis on anti-inflammatory and abscopal effects and the induction of stress-induced anti-tumour immunity.

Effects of 50 Hz sinusoidal magnetic fields on Hsp27, Hsp70, Hsp90 expression in porcine aortic endothelial cells (PAEC).

The aim of the present study was to investigate the influence of 50 Hz sinusoidal magnetic field on Hsp27, Hsp70, and Hsp90 expression in a model of primary culture of porcine aortic endothelial cells (PAEC). We took into consideration the Hsp profile in terms of mRNA expression, protein expression and protein localization inside the cells. The choice of the cell system was motivated by the involvement of the endothelial cells in the onset of many diseases; moreover, only few reports describe the effects of extremely low frequency magnetic fields (ELF-MFs) on such cells. ELF-MF exposure induced an increase in the mRNA levels of the three proteins, which was statistically significant for Hsp70. On the contrary, we did not observe any influence on Hsp27, Hsp70, and Hsp90 protein levels. Analysis in situ by immunofluorescence revealed that ELF-MF exposure affected the cellular distribution of Hsp27; in particular a partial relocalization in the nucleus was observed.

50 Hz magnetic fields activate mussel immunocyte p38 MAP kinase and induce HSP70 and 90.

Fifty hertz magnetic fields (MFs) induced the expression of heat shock proteins (HSPs) 70 and 90 in immunocytes of the mussel Mytilus galloprovincialis. Animals exposed at 300 microT for three different times (30; 2 x 30; 3 x 30 min), did not show differences in the HSP densitometric values in comparison with non-exposed mussels. At 400 microT, exposed animals showed a time-dependent increase in HSP expression as revealed by Western blot. After exposure to 600 microT, the HSP densitometric values were significantly higher than controls but not related to exposure duration. The induction of HSPs is concomitant with the activation of p38 MAP kinase signalling pathway. The present findings suggest the possibility to modulate the expression of HSPs by an appropriate time-intensity magnetic field exposure.

Response of human lymphocytes to low gamma ray doses

Linfocitos humanos fueron irradiados en un campo de radiación gamma de baja intensidad para determinar la expresión de las proteínas de choque calórico en función de la dosis. Los linfocitos fueron obtenidos de individuos cuyo trabajo los identifica como ocupacionalmente expuesto y no ocupacionalmente expuestos. La identidad de las proteínas se realizó utilizando anticuerpos contra las proteínas Hsp25, Hsp60, Hsp70 y Hsp90. De éstas, solamente la proteína hsp70 fue detectada antes y después de la irradiación. Los linfocitos del personal ocupacionalmente expuesto y no ocupacionalmente expuesto expresaron, antes y después de la irradiación, solamente la proteína Hsp70. La cantidad de proteína resultó directamente proporcional al tiempo de irradiación. Después de una dosis gamma de 70.5 mGy, los linfocitos del individuo ocupacionalmente expuesto expresaron una mayor cantidad de proteína Hsp70 que la expresada por los linfocitos del personal no ocupacionalmente expuesto. Este hecho es indicio de que el individuo ocupacionalmente expuesto tiene una mayor tolerancia a los rayos gamma (gamma-tolerancia), inducida por un proceso de adaptación generada por su condición laboral