Thiothymidine plus low-dose UVA kills hyperproliferative human skin cells independently of their human papilloma virus status
Open accessAbstract
The thymidine analogue 4-thiothymidine (S4TdR) is a photosensitizer for UVA radiation. The UV absorbance spectrum of S4TdR and its incorporation into DNA suggests that it might act synergistically with nonlethal doses of UVA to selectively kill hyperproliferative or cancerous skin cells. We show here that nontoxic concentrations of S4TdR combine with nonlethal doses of UVA to kill proliferating cultured skin cells. Established cell lines with a high fraction of proliferating cells were more sensitive than primary keratinocytes or fibroblasts to apoptosis induction by S4TdR/UVA. Although S4TdR plus UVA treatment induces stabilization of p53, cell death, as measured by apoptosis or clonal survival, occurs to a similar extent in both p53 wild-type and p53-null backgrounds. Furthermore, different types of human papilloma virus E6 proteins, which protect against UVB-induced apoptosis, have little effect on killing by S4TdR/UVA. S4TdR/UVA offers a possible therapeutic intervention strategy that seems to be applicable to human papilloma virus–associated skin lesions. [Mol Cancer Ther 2007;6(9):2487–95]
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6-TG incorporation into mitochondrial DNA leads to ROS generation upon UVA irradiation, formation of DNA oxidation products, and loss of mitochondrial function.
“This was found to lead to the generation of ROS upon UVA irradiation with subsequent formation of DNA oxidation products that is accompanied by a loss of mitochondrial function (224).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [224]
6-TG incorporates into mitochondrial DNA of HCT116 human cells.
“Evidence was recently provided for the incorporation of 6-TG in mitochondrial DNA of HCT116 human cells (224).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [224]
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- Authors
- Reelfs, O., Xu, Y.-Z., Massey, A., Karran, P., & Storey, A.
- Affiliations
- Cancer Research UK (GB)
- The Open University (GB)
- Venue
- Molecular Cancer Therapeutics
- Published
- 2007-09-01
- Volume
- 6
- Issue
- 9
- Pages
- 2487-2495
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC2423463
- OpenAlex
- W2124955918
- Cited by
- 30
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 4 · 2016: 1 · 2014: 2 · 2013: 2 · 2012: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Open Research Online - ORO (The Open University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (A6695)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Keywords
- 4-thiothymidine, UVA, photosensitizers, keratinocytes, fibroblasts, apoptosis, p53 stabilization, E6 oncoprotein, selective cell killing
- MeSH terms
- Animals, Cells, Cultured, Combined Modality Therapy, DNA Damage, Female, Fibroblasts, Fibrosarcoma, Flow Cytometry, Humans, Middle Aged, Skin, Skin Neoplasms, Thymidine, Ultraviolet Rays, Blotting, Western, Octreotide, Keratinocytes, Tumor Suppressor Protein p53, Apoptosis, Papillomaviridae, Papillomavirus Infections, Cell Proliferation, Mice
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