Vitamin D3 enhances the apoptotic response of epithelial tumors to aminolevulinate-based photodynamic therapy.
Vitamin D3 enhances the apoptotic response of epithelial tumors to aminolevulinate-based photodynamic therapy.
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DOI：
10.1158/0008-5472.can-11-0805
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发表时间：
2011-09-15
期刊：
影响因子：
11.2
通讯作者：
Maytin EV
中科院分区：
文献类型：
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作者：
Anand S;Wilson C;Hasan T;Maytin EV
由外源性氨基酮丙酸(ALA-PDT)介导的光动力疗法，然后暴露在激光或宽带光源下，是一种很有前途的治疗多种类型癌症的方法，但它仍然不足以治疗大而深的实体肿瘤。在此，我们报道维生素D3的活性形式骨化三醇可以作为一种无毒的预适应方案在ALA之前给予，以显著提高ALA-PDT的疗效。使用小鼠鳞状皮肤癌模型进行临床前概念验证，我们发现，局部或腹膜内给予骨化三醇可使PDT激活的ALA产物原卟啉-IX(PpIX)的肿瘤积聚增加10倍，主要是通过改变卟啉合成酶协同卟啉原氧化酶(增加)和铁络合酶(减少)的表达。在ALA为基础的光动力疗法后，骨化三醇预处理的肿瘤经历了增强的细胞凋亡死亡。机制研究证明，在ALA-PDT前，骨化三醇预处理的肿瘤中，激活了外在的凋亡途径，特异性地切割了caspase-8，增加了肿瘤坏死因子α的产生。极低剂量的骨化三醇(0.1-1微克/公斤体重)足以诱导对ALA-PDT疗效的肿瘤选择性增强，使毒性问题可以忽略不计。我们的发现确定了一种简单、无毒和高效的预适应方案来增强上皮性肿瘤对ALA-PDT的反应，可能通过选择性地增强光敏剂PPIX和肿瘤坏死因子α在肿瘤中的积聚来扩大其临床应用。
Photodynamic therapy, mediated by exogenously administered aminolevulinic acid (ALA-PDT) followed by exposure to a laser or broadband light source, is a promising modality for treatment of many types of cancers, but it remains inadequate to treat large, deep solid tumors. Here we report that calcitriol, the active form of Vitamin D3, can be administered prior to ALA as a non-toxic preconditioning regimen to markedly increase the efficacy of ALA-PDT. Using mouse models of squamous skin cancer for preclinical proof of concept, we showed that calcitriol delivered topically or intraperitoneally increased tumoral accumulation of the PDT-activated ALA product protoporphyrin-IX (PpIX) up to 10-fold, mainly by altering expression of the porphyrin synthesis enzymes coproporphyrinogen oxidase (increased) and ferrochelatase (decreased). Calcitriol-pretreated tumors underwent enhanced apoptotic cell death following ALA-based PDT. Mechanistic studies documented activation of the extrinsic apoptotic pathway, with specific cleavage of caspase-8 and increased production of TNFα in tumors preconditioned by calcitriol treatment before ALA-PDT. Very low doses of calcitriol (0.1–1 µg/kg body weight) were sufficient to elicit tumor-selective enhancement to ALA-PDT efficacy, rendering toxicity concerns negligible. Our findings define a simple, non-toxic and highly effective preconditioning regimen to enhance the response of epithelial tumors to ALA-PDT, possibly broadening its clinical applications by selectively enhancing accumulation of photosensitizer PpIX along with TNFα in tumors.