Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Pro-tumor Bystander Effects of Nitric Oxide in Anti-tumor Photodynamic Therapy

Version 1 : Received: 23 April 2023 / Approved: 24 April 2023 / Online: 24 April 2023 (04:26:43 CEST)

How to cite: Girotti, A.W.; Bazak, J.; Korytowski, W. Pro-tumor Bystander Effects of Nitric Oxide in Anti-tumor Photodynamic Therapy. Preprints 2023, 2023040819. https://doi.org/10.20944/preprints202304.0819.v1 Girotti, A.W.; Bazak, J.; Korytowski, W. Pro-tumor Bystander Effects of Nitric Oxide in Anti-tumor Photodynamic Therapy. Preprints 2023, 2023040819. https://doi.org/10.20944/preprints202304.0819.v1

Abstract

Recent studies have revealed that several cancer cell types can upregulate inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) after a moderate photodynamic challenge sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin-IX. The NO signaled for cell resistance to photokilling as well as greater growth and migration/invasion aggressiveness of surviving cells. On this basis, it was predicted that diffusible NO from PDT-targeted cells in a tumor might enhance growth, migration, and invasiveness of non- or poorly PDT-targeted bystander cells. This was tested using a novel approach in which ALA-PDT targeted cancer cells on a culture dish were initially segregated from non-targeted bystander cells of the same type via impermeable silicone-rimmed rings. Several hours after LED irradiation, the rings were removed, and both cell populations analyzed in the dark for various responses. After a moderate extent of targeted cell killing (~25%), bystander proliferation and migration were evaluated, and both were found to be significantly enhanced. Enhancement corelated with iNOS/NO upregulation in surviving PDT-targeted cancer cells in the following cell type order: PC3 > MDA-MB-231 >U87 > BLM. If occurring in an actual PDT-challenged tumor, such bystander effects might compromise treatment efficacy by stimulating tumor growth and/or metastatic dissemination. Possible mitigation of these negative effects by using pharmacologic inhibitors of iNOS expression or activity as PDT adjuvants will be discussed.

Keywords

PDT; Nitric oxide; iNOS/NO induction; Bystander effects

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

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