Vitamin D3 enhances the apoptotic response of epithelial tumors to aminolevulinate-based photodynamic therapy

Cancer Res. 2011 Sep 15;71(18):6040-50. doi: 10.1158/0008-5472.CAN-11-0805. Epub 2011 Aug 1.


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; however, it remains inadequate to treat large, deep, solid tumors. In this article, we report that calcitriol, the active form of vitamin D3, can be administered before ALA as a nontoxic preconditioning regimen to markedly increase the efficacy of ALA-PDT. Using mouse models of squamous cell 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 after ALA-based PDT. Mechanistic studies have documented activation of the extrinsic apoptotic pathway, with specific cleavage of caspase-8 and increased production of TNF-α in tumors preconditioned by calcitriol treatment before receiving 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, nontoxic, 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 together with TNF-α in tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminolevulinic Acid / pharmacokinetics
  • Aminolevulinic Acid / pharmacology*
  • Animals
  • Calcitriol / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Cell Differentiation / drug effects
  • Cell Growth Processes / drug effects
  • Drug Synergism
  • Humans
  • Mice
  • Photochemotherapy / methods*
  • Photosensitizing Agents / pharmacokinetics
  • Photosensitizing Agents / pharmacology*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Xenograft Model Antitumor Assays


  • Photosensitizing Agents
  • Tumor Necrosis Factor-alpha
  • Aminolevulinic Acid
  • Caspase 3
  • Caspase 8
  • Calcitriol