Photosensitization by iodinated DNA minor groove binding ligands: Evaluation of DNA double-strand break induction and repair
► Photochemotherapy is widely used for psoriasis and cutaneous T-cell lymphoma. ► Ortho-iodoHoechst (UV A Sens) is an extremely potent UVA photosensitizer. ► Ortho-iodoHoechst forms DNA double-strand breaks which are not readily repaired by cells. ► Trichostatin A, augments the DNA damage induced by...
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Published in | Journal of photochemistry and photobiology. B, Biology Vol. 103; no. 2; pp. 145 - 152 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Elsevier B.V
03.05.2011
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Subjects | |
Online Access | Get full text |
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Summary: | ► Photochemotherapy is widely used for psoriasis and cutaneous T-cell lymphoma. ►
Ortho-iodoHoechst (UV
A
Sens) is an extremely potent UVA photosensitizer. ►
Ortho-iodoHoechst forms DNA double-strand breaks which are not readily repaired by cells. ► Trichostatin A, augments the DNA damage induced by
ortho-iodoHoechst.
Iodinated DNA minor groove binding bibenzimidazoles represent a unique class of UVA photosensitizer and their extreme photopotency has been previously characterized. Earlier studies have included a comparison of three isomers, referred to as
ortho-,
meta- and
para-iodoHoechst, which differ only in the location of the iodine substituent in the phenyl ring of the bibenzimidazole. DNA breakage and clonogenic survival studies in human erythroleukemic K562 cells have highlighted the higher photo-efficiency of the
ortho-isomer (subsequently designated UV
A
Sens) compared to the
meta- and
para-isomers. In this study, the aim was to compare the induction and repair of DNA double-strand breaks induced by the three isomers in K562 cells. Further, we examined the effects of the prototypical broad-spectrum histone deacetylase inhibitor, Trichostatin A, on
ortho-iodoHoechst/UVA-induced double-strand breaks in K562 cells. Using γH2AX as a molecular marker of the DNA lesions, our findings indicate a disparity in the induction and particularly, in the repair kinetics of double-strand breaks for the three isomers. The accumulation of γH2AX foci induced by the
meta- and
para-isomers returned to background levels within 24 and 48
h, respectively; the number of γH2AX foci induced by
ortho-iodoHoechst remained elevated even after incubation for 96
h post-irradiation. These findings provide further evidence that the extreme photopotency of
ortho-iodoHoechst is due to not only to the high quantum yield of dehalogenation, but also to the severity of the DNA lesions which are not readily repaired. Finally, our findings which indicate that Trichostatin A has a remarkable potentiating effect on
ortho-iodoHoechst/UVA-induced DNA lesions are encouraging, particularly in the context of cutaneous T-cell lymphoma, for which a histone deacetylase inhibitor is already approved for therapy. This finding prompts further evaluation of the potential of combination therapies. |
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Bibliography: | http://dx.doi.org/10.1016/j.jphotobiol.2011.02.022 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 1011-1344 1873-2682 |
DOI: | 10.1016/j.jphotobiol.2011.02.022 |