Bystander Effects Induced by Diffusing Mediators after Photodynamic Stress

Abstract

The bystander effect, whereby cells that are not traversed by ionizing radiation exhibit various responses when in proximity to irradiated cells, is well documented in the field of radiation biology, Here we demonstrate that considerable bystander responses are also observed after photodynamic stress using the membrane-localizing dye deuteroporphyrin (DP). Using cells of a WTK1 human lymphoblastoid cell line in suspension and a transwell insert system that precludes contact between targeted and bystander cells, we have shown that the bystander signaling is mediated by diffusing species. The extranuclear localization of the photosensitizer used suggests that primary DNA damage is not the trigger for initiating these bystander responses, which include elevated oxidative stress, DNA damage (micronucleus formation), mutagenesis and decreased clonogenic survival. In addition, oxidative stress in the bystander population was reduced by the presence of the membrane antioxidant vitamin E in the targeted cells, suggesting that lipid peroxidation may play a key role in mediating these bystander effects. The fluence responses for these bystander effects are non-linear, with larger effects seen at lower fluences and toxicity to the target cell population. Hence, when considering outcomes of photodynamic action in cells and tissue, bystander effects may be significant, especially at sublethal fluences.

High dose bystander effects in spatially fractionated radiation therapy

“…Chemotherapeutic drugs, such as chloroethylnitrosurea [59], paclitaxel [60], mitomycin C [61,62] and phleomycin [61] can induce bystander effects through secretion of media soluble factors. In addition, photosensitizers [63], heat [64] and photodynamic stress [65] have all been reported to cause some type of bystander effect. Therefore, the true nature of bystander effects appears to be a cell-stress related phenomenon and not necessarily a unique by-product of radiation damage or a specific type of treatment.…”

The Role of Mitochondria in the Radiation-Induced Bystander Effect in Human Lymphoblastoid Cells

“…Cells directly exposed to ionizing radiation or chemicals, and those exposed to media from treated cells, show involvement of MAPK pathways (Asur et al, 2009a, Dent et al, 2003. The other stress factors that lead to bystander responses include ultraviolet light (Banerjee et al, 2005) and photodynamic stress (Chakraborty et al, 2009).…”

Photoactivated hypericin increases the expression of SOD-2 and makes MCF-7 cells resistant to photodynamic therapy

“…Although singlet oxygen plays the most important role in cytotoxic effects induced by PDT, there are many other ROS generated by PDT such as superoxide anion, hydroxyl radical and hydrogen peroxide (short-lived) as well as peroxidized reaction products (longer lifetime) such as lipids and proteins, which can directly or indirectly damage tumor cells [23][24][25]. In this regard, bystander effects, especially at sublethal fluences, could also have a significant effect on cancer cells [26]. Moreover, our previous study has confirmed biological activity of singlet oxygen when trolox prevented PDT-induced decrease in HER2 mRNA level in SKBR-3 cells [9].…”