Cited by 114Photodynamic Therapy Research StudiesPorphyrin Metabolism and DisordersNanoplatforms for cancer theranostics

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

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Sinha, A K, Anand, S, Ortel, B J, Chang, Y, Mai, Z, Hasan, T, Maytin, E V·2006·British Journal of Cancer

Abstract

Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) to drive production of an intracellular photosensitiser, protoporphyrin IX (PpIX), is a promising cancer treatment. However, ALA-PDT is still suboptimal for thick or refractory tumours. Searching for new approaches, we tested a known inducer of cellular differentiation, methotrexate (MTX), in combination with ALA-PDT in LNCaP cells. Methotrexate alone promoted growth arrest, differentiation, and apoptosis. Methotrexate pretreatment (1 mg l(-1), 72 h) followed by ALA (0.3 mM, 4 h) resulted in a three-fold increase in intracellular PpIX, by biochemical and confocal analyses. After exposure to 512 nm light, killing was significantly enhanced in MTX-preconditioned cells. The reverse order of treatments, ALA-PDT followed by MTX, yielded no enhancement. Methotrexate caused a similar relative increase in PpIX, whether cells were incubated with ALA, methyl-ALA, or hexyl-ALA, arguing against a major effect upon ALA transport. Searching for an effect among porphyrin synthetic enzymes, we found that coproporphyrinogen oxidase (CPO) was increased three-fold by MTX at the mRNA and protein levels. Transfection of LNCaP cells with a CPO-expressing vector stimulated the accumulation of PpIX. Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers.

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  • Pretreatment of LNCaP tumor cells with methotrexate significantly improved ALA-PDT efficacy, related to increased synthesis of coproporphyrinogen oxidase, which stimulated accumulation of PpIX.

    “Furthermore, it has been revealed that pretreatment of LNCaP tumor cells with methotrexate significantly improved ALA-PDT efficacy. This effect was related to increased synthesis of coproporphyrinogen oxidase, which stimulated the accumulation of PpIX [47].”

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Authors
Sinha, A. K., Anand, S., Ortel, B. J., Chang, Y., Mai, Z., Hasan, T., & Maytin, E. V.
Affiliations
  • Harvard University (US)
  • Cleveland Clinic (US)
Corresponding author
Maytin, E V
Venue
British Journal of Cancer
Published
2006-07-25
Volume
95
Issue
4
Pages
485-495
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
OpenAlex
W1994983260
Cited by
114
References
35
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 2 · 2020: 9 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 12 · 2013: 4 · 2012: 9
FWCI
5.62
Type
journal article
Language
en
Open access
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Kansai Medical University
  • National Institutes of Health
  • Directorate for Biological Sciences
  • National Cancer Institute (P01 CA84203, P01CA084203)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords
methotrexate, 5-aminolevulinic acid, photodynamic therapy, prostate cancer, protoporphyrin IX, coproporphyrinogen oxidase, LNCaP cells, combination therapy, porphyrin synthesis, apoptosis, cell differentiation
MeSH terms
Aminolevulinic Acid, Cell Differentiation, Cell Survival, Coproporphyrinogen Oxidase, Humans, Male, Methotrexate, Models, Biological, Photochemotherapy, Prostatic Neoplasms, Protoporphyrins, Metribolone, Up-Regulation, Apoptosis, Photosensitizing Agents, Cell Line, Tumor, Cell Proliferation

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