Girotti Albert W, Fahey Jonathan M, Korytowski Witold
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226- 3548, USA.
Curr Med Chem. 2016;23(24):2754-2769. doi: 10.2174/0929867323666160812145641.
Photodynamic therapy (PDT) is a unique site-specific treatment for eradicating a variety of solid tumors, including prostate, lung, bladder, and brain tumors. PDT is a three-component modality involving (i) administration of a photosensitizing agent (PS), (ii) PS photoexcitation by visible or near-infrared light, and (iii) molecular oxygen. Upon photoexcitation, PS gives rise to tumor-damaging reactive oxygen species, most prominently singlet oxygen (1O2). Previous studies revealed that endogenous nitric oxide (NO) in various mouse tumor models significantly reduced PDT effectiveness. Recent studies in the authors' laboratory indicated that NO produced by photostressed tumor cells per se can elicit anti-PDT effects. For example, breast cancer COH-BR1 and prostate cancer PC3 cells exhibited a rapid and prolonged upregulation of inducible nitric oxide synthase (iNOS) after sensitization with 5- aminolevulinic acid (ALA)-induced protoporphyrin-IX, followed by broad-band visible irradiation. Use of iNOS inhibitors and NO scavengers demonstrated that iNOS/NO played a key role in cell resistance to apoptotic photokilling. Moreover, cells surviving an ALA/light challenge proliferated, migrated, and invaded more rapidly than controls, again in iNOS/NOdependent fashion. Thus, NO was found to play a crucial role in various manifestations of enhanced aggressiveness exhibited by remaining live cells. Recent work has revealed that induced NO in PDT-targeted PC3 cells can also translocate and increase aggressiveness of non-targeted bystander cells. These negative and potentially tumor-promoting side effects of NO in PDT may be averted through use of iNOS inhibitors as adjuvants. Each of the above aspects of PDT antagonism by NO will be discussed in this review.
光动力疗法（PDT）是一种独特的针对特定部位的治疗方法，可用于根除多种实体瘤，包括前列腺癌、肺癌、膀胱癌和脑肿瘤。PDT是一种由三部分组成的治疗方式，包括：（i）给予光敏剂（PS）；（ii）用可见光或近红外光对PS进行光激发；（iii）分子氧。光激发后，PS会产生对肿瘤有损害作用的活性氧，其中最主要的是单线态氧（1O2）。先前的研究表明，在各种小鼠肿瘤模型中，内源性一氧化氮（NO）会显著降低PDT的疗效。作者实验室最近的研究表明，光应激肿瘤细胞本身产生的NO可引发抗PDT效应。例如，用5-氨基酮戊酸（ALA）诱导的原卟啉-IX致敏后，再进行宽带可见光照射，乳腺癌COH-BR1细胞和前列腺癌PC3细胞会迅速且持续地上调诱导型一氧化氮合酶（iNOS）。使用iNOS抑制剂和NO清除剂表明，iNOS/NO在细胞对凋亡性光杀伤的抗性中起关键作用。此外，在ALA/光照刺激下存活的细胞比对照细胞增殖、迁移和侵袭得更快，同样是以iNOS/NO依赖的方式。因此，发现NO在存活的活细胞表现出的增强侵袭性的各种表现中起关键作用。最近的研究表明，在PDT靶向的PC3细胞中诱导产生的NO也可以转移并增加非靶向旁观者细胞的侵袭性。通过使用iNOS抑制剂作为佐剂，可以避免NO在PDT中产生的这些负面且可能促进肿瘤生长的副作用。本文将讨论NO对PDT拮抗作用的上述各个方面。
