Abstract
Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca(2+)-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.
Highlights
The phrase “bystander effects” was initially adopted in a radiotherapy context to account for responses observed in cellular systems that have not been directly traversed by ionizing radiations but are in close proximity to irradiated cells [1, 2]
The process ensued in near-complete depopulation of the field of view within 24 h following focal photodynamic injury (Figure 1d). ∆Ca2+, ∆Nitric oxide (NO) and cytochrome c signals were never detected during or after laser irradiation at 671 nm if AlClPc was omitted from the loading solution (3 out of 3 cultures)
The overall goal of this study was to investigate the interplay between bystander NO and Ca2+ signaling and the role played by gap junction communication in photodynamic therapy
Summary
The phrase “bystander effects” was initially adopted in a radiotherapy context to account for responses observed in cellular systems that have not been directly traversed by ionizing radiations but are in close proximity to irradiated cells [1, 2]. Bystander effects triggered by ionizing radiations in tumor and tumor-infiltrating cells include altered gene expression, DNA damage, mutation, malignant transformation and cell death [3,4,5,6,7,8,9]. Bystander responses have been observed as a consequence of other insults including ultraviolet radiation, heat, chemotherapy agents and photodynamic therapy; the underlying mechanism and role in clinically relevant scenarios remain incompletely defined [1, 2]. NO production by nitric oxide synthases (NOS) is controlled by enzyme binding to calmodulin (CaM)[27]; full activation of target proteins by CaM typically requires occupancy of its four Ca2+−binding sites [28]
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