Abstract
Tumor cells exposed to stress-inducing radiotherapy or chemotherapy can send signals to non- or minimally exposed bystander cells. Bystander effects of ionizing radiation are well established, but little is known about such effects in non-ionizing photodynamic therapy (PDT). Our previous studies revealed that several cancer cell types upregulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after a moderate 5-aminolevulinic acid (ALA)-based PDT challenge. The NO signaled for cell resistance to photokilling as well as greater growth, migration and invasion of surviving cells. Based on this work, we hypothesized that diffusible NO produced by PDT-targeted cells in a tumor might elicit pro-growth/migration responses in non-targeted bystander cells. In the present study, we tested this using a novel approach, in which ALA-PDT-targeted human cancer cells on culture dishes (prostate PC3, breast MDA-MB-231, glioma U87, or melanoma BLM) were initially segregated from non-targeted bystanders via impermeable silicone-rimmed rings. Several hours after LED irradiation, rings were removed, and both cell populations analyzed for various post-hν responses. For a moderate and uniform level of targeted cell killing by PDT (~25%), bystander proliferation and migration were both enhanced. Enhancement correlated with iNOS/NO upregulation in surviving targeted cells in the following order: PC3 > MDA-MB-231 > U87 > BLM. If occurring in an actual tumor PDT setting and not suppressed (e.g., by iNOS activity or transcription inhibitors), then such effects could compromise treatment efficacy or even stimulate disease progression if PDT’s anti-tumor potency is not great enough.
Highlights
Relevant photodynamic therapy (PDT) was introduced about 45 years ago as a novel means for selectively eradicating a variety of solid tumors via cytotoxic photochemistry [1,2].As an anti-tumor modality, PDT is unique in requiring three components: a photosensitizing agent (PS), PS-exciting light in the far-visible-to-near-infrared range, and molecular oxygen [3,4,5,6].PS photoexcitation during PDT gives rise to cytotoxic reactive oxygen species (ROS) such as singlet oxygen (1 O2 )
We discovered that various cancer cell lines significantly upregulate cytoprotective inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after a moderate photodynamic challenge sensitized by aminolevulinic acid (ALA)-induced PpIX [16,17,18]
The results described provide additional support for our hypothesis that NO diffusing from upregulated iNOS in targeted cells played a key signaling role in the stimulation of bystander aggressiveness
Summary
Relevant photodynamic therapy (PDT) was introduced about 45 years ago as a novel means for selectively eradicating a variety of solid tumors via cytotoxic photochemistry [1,2]. PS photoexcitation during PDT gives rise to cytotoxic reactive oxygen species (ROS) such as singlet oxygen (1 O2 ). The first PS to receive FDA approval for PDT applications was Photofrin® , an oligomeric form of hematoporphyrin that continues to be used for a variety of malignancies [4,5,6]. PDT can often overcome the innate or acquired resistance to other therapies that many tumors exhibit [5]. In addition to pre-existing administered sensitizers such as Photofrin® , pro-sensitizers have been developed, one common example being 5-aminolevulinic acid (ALA). Upon entering cancer cells via an amino acid transporter [7], ALA is metabolized to Cancers 2019, 11, 1674; doi:10.3390/cancers11111674 www.mdpi.com/journal/cancers
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