Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells
Open accessAbstract
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].”
From Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer (2011) · cites this paper as [47]
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Self-citation
- 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
- PMC
- PMC2360674
- 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
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- 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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