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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-? in tumors preconditioned by calcitriol treatment before receiving ALA-PDT. Very low doses of calcitriol (0.1-1 ?g/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-? in tumors.

SUBMITTER: Anand S

PROVIDER: S-EPMC3360482 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Anand Sanjay S Wilson Clara C Hasan Tayyaba T Maytin Edward V EV

Cancer research 20110801 18

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 ...[more]

PMID: 21807844

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Project description:BackgroundMethyl-aminolevulinate photodynamic therapy (MAL-PDT) is an excellent option for the treatment of basal cell carcinoma (BCC). However, up to 25% of cases are resistant to this treatment modality.ObjectiveThe aim of this study was to identify potential biomarkers of BCC response to MAL-PDT.Material and methodsClinical, histological, and immunohistochemical (p53, Ki-67, CD-31, COX2, β-catenin, EGFR, and survivin) variables were analyzed in a retrospective study of consecutive BCC patients treated with MAL-PDT at the San Jorge Hospital, Huesca, Spain between January 2006 and December 2015. To deepen on these markers, the effects on p53 and cyclin D1 expression, in vitro response to MAL-PDT of 2 murine BCC cell lines (ASZ and BSZ), was also evaluated.ResultsThe retrospective study examined the response to MAL-PDT of 390 BCCs from 182 patients. The overall clinical response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46). Immunohistochemistry revealed positive p53 in 84.6% of responders but only 15.4% of nonresponsive tumors (p = 0.011). Tumors with increased peripheral palisading of basal cell islands to immunostaining β-catenin responded poorly to PDT (p = 0.01). In line with our findings in patients, in vitro studies revealed a better response to PDT in the p53-positive ASZ cell line than the p53-negative BSZ cell line (p<0.01). Multivariate analysis revealed that the following variables were significantly associated with response to PDT: age, nBCC, presence of peritumoral inflammatory infiltrate, and p53 immunopositivity. Patients with positive p53 immunostaining were 68.54 times more likely to achieve cure than p53-negative patients (CI95% 2.94-159.8).ConclusionOur finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapy.

Project description:This proteomic study This proteomic study focuses on the role of reversible thiol oxidation after hexyl aminolevulinate mediated PDT (HAL-PDT). The human epidermoid carcinoma cell line A431 was used as model system and red light as light source, a clinical relevant in vitro model. The light dose dependent cell cytotoxicity was measured by resazurin assay. The most clinical relevant dose, LD100, was used for the proteomic part of the study and cells where harvested 30 min after treatment. The reversibly oxidized thiol proteins were selected by biotinylation and identified by mass spectrometry. This proteomic technique revealed over 1100 thiol proteins which were reversibly oxidized after HAL-PDT. Identified proteins were analysed by bioinformatics (IPA and GO) and a list of reliable identified proteins (282 proteins) where further analysed. Both the cellular location and function was determined for these proteins. In addition, 18 of the proteins where identified as redox regulated, 36 to be a part of the apoptotic pathway and 9 to be both redox regulated and a part of apoptotic pathway. From these results we suggest redox regulated proteins as a trigger mechanism for PDT induced apoptosis.focuses on the role of reversible thiol oxidation after hexyl aminolevulinate mediated PDT (HAL-PDT). The human epidermoid carcinoma cell line A431 was used as model system and red light as light source, a clinical relevant in vitro model. The light dose dependent cell cytotoxicity was measured by resazurin assay. The most clinical relevant dose, LD100, was used for the proteomic part of the study and cells where harvested 30 min after treatment. The reversibly oxidized thiol proteins were selected by biotinylation and identified by mass spectrometry. This proteomic technique revealed over 1100 thiol proteins which were reversibly oxidized after HAL-PDT. Identified proteins were analysed by bioinformatics (IPA and GO) and a list of reliable identified proteins (282 proteins) where further analysed. Both the cellular location and function was determined for these proteins. In addition, 18 of the proteins where identified as redox regulated, 36 to be a part of the apoptotic pathway and 9 to be both redox regulated and a part of apoptotic pathway. From these results we suggest redox regulated proteins as a trigger mechanism for PDT induced apoptosis.

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

Publications

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

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