Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive a...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2017-05, Vol.12 (5), p.e0178493
Main Authors: Lee, Ming-Jen, Hung, Shih-Hsuan, Huang, Mu-Ching, Tsai, Tsuimin, Chen, Chin-Tin
Format: Article
Language:English
Subjects:
Acids
Aminolevulinic acid
Aminolevulinic Acid - pharmacology
Animal models
Animals
Antibiotics
Antibiotics, Antineoplastic - pharmacology
Anticancer properties
Antitumor activity
Apoptosis
Benign
Biocompatibility
Biology and Life Sciences
Biotechnology
Cancer
Cell death
Cell Line, Tumor
Cell survival
Clinical trials
Combined treatment
Complications and side effects
Cytotoxicity
Disease
Disorders
Dosage and administration
Doxycycline
Doxycycline - pharmacology
Drug therapy
Enzymes
Ferrochelatase
Fibroblasts
Genetic disorders
Humans
Hydroxymethylbilane synthase
Laboratories
Medicine and Health Sciences
Metastases
Minocycline
Morbidity
Neoplasia
Neoplasms
Nervous system tumors
Neurilemmoma - pathology
Neurofibromatosis
Neurological disorders
Oral cancer
Phenols
Photochemotherapy
Photodynamic therapy
Photosensitizing Agents - pharmacology
Plexiform neurofibroma
Protein synthesis
Protoporphyrin
Protoporphyrin IX
Radiation
Recklinghausen's disease
Research and Analysis Methods
Side effects
Skin
Synergistic effect
Tumor cell lines
Tumor cells
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0178493