title: Vitamin D3 enhances the apoptotic response of epithelial tumors to aminolevulinate-based photodynamic therapy.
abstract: 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.
authors.affiliation: Department of Dermatology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Anand
authors.forename: Clara
authors.initials: C
authors.lastname: Wilson
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
authors.forename: Edward V
authors.initials: EV
authors.lastname: Maytin
mesh_terms: D000622:Aminolevulinic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D014409:Tumor Necrosis Factor-alpha; D000622:Aminolevulinic Acid; D053148:Caspase 3; D053181:Caspase 8; D002117:Calcitriol