Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Biophysics, Jagiellonian University, 31-007 Krakow, Poland.
Int J Mol Sci. 2023 Jul 17;24(14):11559. doi: 10.3390/ijms241411559.
Various studies have revealed that several cancer cell types can upregulate inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) after moderate photodynamic treatment (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin-IX. As will be discussed, the NO signaled cell resistance to photokilling as well as greater growth and migratory aggressiveness of surviving cells. On this basis, it was predicted that diffusible NO from PDT-targeted cells in a tumor might enhance the 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 were 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 correlated 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. Mitigation of these and other negative NO effects using pharmacologic adjuvants that either inhibit iNOS transcription or enzymatic activity will be discussed.
各种研究表明，几种癌细胞类型在 5-氨基酮戊酸（ALA）诱导的原卟啉-IX 敏化的适度光动力治疗（PDT）后可以上调诱导型一氧化氮合酶（iNOS）和 iNOS 衍生的一氧化氮（NO）。正如将要讨论的那样，NO 信号细胞对光杀伤的抗性以及存活细胞的生长和迁移侵袭性增加。在此基础上，预测肿瘤中 PDT 靶向细胞释放的扩散性 NO 可能增强非 PDT 靶向或 PDT 靶向性差的旁观者细胞的生长、迁移和侵袭性。这是通过一种新方法进行测试的，其中在培养皿上用 ALA-PDT 靶向癌细胞最初通过不可渗透的硅酮边框环与相同类型的非靶向旁观者细胞分开。在 LED 照射数小时后，去除环，并在黑暗中分析两种细胞群的各种反应。在靶向细胞杀伤达到适度程度（约 25%）后，评估了旁观者细胞的增殖和迁移，发现两者均显著增强。增强与存活的 PDT 靶向癌细胞中的 iNOS/NO 上调相关，以下按细胞类型顺序排列：PC3 > MDA-MB-231 > U87 > BLM。如果发生在实际的 PDT 挑战肿瘤中，这种旁观者效应可能会通过刺激肿瘤生长和/或转移扩散来损害治疗效果。将讨论使用药理学佐剂来减轻这些和其他负性 NO 效应，这些佐剂可以抑制 iNOS 转录或酶活性。
