Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Dose dependent sun protective effect of topical melatonin: A randomized, placebo-controlled, double-blind study

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. MicroRNAs and potential target interactions in psoriasis

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Subdermal penetration of topically applied clobetasol propionate in ointment base through intact human skin

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Patient-reported Outcomes During Treatment in Patients with Moderate-to-severe Psoriasis: A Danish Nationwide Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Skin Patterning in Psoriasis by Spatial Interactions between Pathogenic Cytokines

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. High-Throughput Sequencing-Based Investigation of Viruses in Human Cancers by Multienrichment Approach

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

BACKGROUND: Psoralen plus ultraviolet A (PUVA) photochemotherapy is a combination treatment used for inflammatory and neoplastic skin diseases such as mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). However, 30% of MF patients do not respond sufficiently to PUVA and require more aggressive therapies.

OBJECTIVE: The aim of this project was to investigate whether inhibition of Ataxia Telangiectasia and Rad3 related kinase (ATR) may enhance efficacy of phototherapy.

METHODS: CTCL cell lines (MyLa2000, SeAx and Mac2a) served as in vitro cell models. ATR and Chk1 were inhibited by small molecule antagonists VE-821, VE-822 or Chir-124, or by small interfering RNAs (siRNAs). Cell cycle and viability were assessed by flow cytometry.

RESULTS: Small molecule inhibitors of ATR and Chk1 potently sensitized all cell lines to PUVA and, importantly, also to UVA, which by itself did not cause apoptotic response. VE-821/2 blocked ATR pathway activation and released the cells from the G2/M block caused by UVA and PUVA, but did not affect apoptosis caused by other chemotherapeutics (etoposide, gemcitabine, doxorubicine) or by hydrogen peroxide. Knockdown of ATR and Chk1 with siRNA also blocked the ATR pathway and released the cells from G2/M block but did not sensitize the cells to UVA as observed with the small molecule inhibitors. The latter suggested that the synergism between VE-821/2 or Chir-124 and UVA was not solely caused by specific blocking of ATR kinase but also ATR-independent photosensitization. This hypothesis was further verified by administrating VE-821/2 or Chir-124 before and after UVA irradiation, as well as comparing their activity with other ATR and Chk1 inhibitors (AZD6738 and MK8776). We found that only VE-821/2 and Chir-124 kinase inhibitors had synergistic effect with UVA, and only if applied before treatment with UVA.

CONCLUSION: Small molecule ATR and Chk1 inhibitors potently sensitize lymphoma cells to UVA radiation and induce a prominent apoptotic response. Interestingly, this effect is due to the dual (kinase inhibiting and photosensitizing) mode of action of these compounds.

Original languageEnglish
JournalJournal of Dermatological Science
Volume84
Issue number3
Pages (from-to)239-247
Number of pages9
ISSN0923-1811
DOIs
Publication statusPublished - Dec 2016

ID: 49766769