Solban Nicolas, Selbo Pål K, Sinha Alok K, Chang Sung K, Hasan Tayyaba
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Cancer Res. 2006 Jun 1;66(11):5633-40. doi: 10.1158/0008-5472.CAN-06-0604.
Photodynamic therapy (PDT) is now an approved therapeutic modality, and induction of vascular endothelial growth factor (VEGF) following subcurative PDT is of concern as VEGF may provide a survival stimulus to tumors. The processes that limit the efficacy of PDT warrant investigation so that mechanism-based interventions may be developed. This study investigates VEGF increase following subcurative PDT using the photosensitizer benzoporphyrin derivative (BPD) both in an in vitro and in an orthotopic model of prostate cancer using the human prostate cancer cell line LNCaP. The two subcurative doses used, 0.25 and 0.5 J/cm(2), mimicked subcurative PDT and elicited a 1.6- and 2.1-fold increase, respectively, in secreted VEGF 24 hours following PDT. Intracellular VEGF protein measurement and VEGF mRNA showed a 1.4- and 1.6-fold increase only at 0.5 J/cm(2). In vivo subcurative PDT showed an increase in VEGF by both immunohistochemistry and ELISA. In vitro analysis showed no activation of hypoxia-inducible factor-1alpha (HIF-1alpha) or cyclooxygenase-2 (COX-2) following subcurative PDT; furthermore, small interfering RNA inhibition of HIF-1alpha and COX-2 inhibitor treatment had no effect on PDT induction of VEGF. PDT in the presence of phosphatidylinositol 3-kinase/AKT inhibitor or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase inhibitor still induced VEGF. However, subcurative PDT increased phosphorylated p38 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase. The p38 MAPK inhibitor abolished PDT induction of VEGF. The results establish the importance of VEGF in subcurative BPD-PDT of prostate cancer and suggest possible molecular pathways for its induction. These findings should provide the basis for the development of molecular-based interventions for enhancing PDT and merit further studies.
光动力疗法（PDT）现已成为一种获批的治疗方式，而亚治愈性PDT后血管内皮生长因子（VEGF）的诱导令人担忧，因为VEGF可能为肿瘤提供生存刺激。限制PDT疗效的过程值得研究，以便开发基于机制的干预措施。本研究使用人前列腺癌细胞系LNCaP，在前列腺癌的体外和原位模型中，研究了使用光敏剂苯并卟啉衍生物（BPD）进行亚治愈性PDT后VEGF的增加情况。所使用的两个亚治愈剂量，即0.25和0.5 J/cm²，模拟亚治愈性PDT，分别在PDT后24小时使分泌的VEGF增加了1.6倍和2.1倍。细胞内VEGF蛋白测量和VEGF mRNA仅在0.5 J/cm²时分别增加了1.4倍和1.6倍。体内亚治愈性PDT通过免疫组织化学和酶联免疫吸附测定法均显示VEGF增加。体外分析表明，亚治愈性PDT后缺氧诱导因子-1α（HIF-1α）或环氧合酶-2（COX-2）未被激活；此外，HIF-1α的小干扰RNA抑制和COX-2抑制剂处理对PDT诱导VEGF没有影响。在磷脂酰肌醇3-激酶/AKT抑制剂或丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶抑制剂存在的情况下，PDT仍可诱导VEGF。然而，亚治愈性PDT增加了磷酸化的p38和应激激活蛋白激酶/c-Jun氨基末端激酶。p38 MAPK抑制剂消除了PDT对VEGF的诱导。这些结果确立了VEGF在前列腺癌亚治愈性BPD-PDT中的重要性，并提示了其诱导的可能分子途径。这些发现应为开发增强PDT的基于分子的干预措施提供依据，并值得进一步研究。
