Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer

Victoria L. Luchenko, Crystal D. Salcido, Yongwei Zhang, Keli Agama, Edina Komlodi-Pasztor, Robert F. Murphy, Giuseppe Giaccone, Yves Pommier, Susan E. Bates, Lyuba Varticovski

Research output: Contribution to journalArticlepeer-review

Abstract

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype in need of better therapies. Histone deacetylase inhibitors (HDIs) promote increased lysine acetylation in nucleosomal histones, and are thought to relax chromatin, thereby allowing increased access of transcription factors and DNA damaging agents alike to DNA. We studied whether two HDIs, belinostat and romidepsin, can be effectively combined with cisplatin or etoposide (VP-16) for SCLC cells. Analysis of cell survival and synergy was performed using CalcuSyn mathematical modeling to calculate a combination index. Immunostaining of γH2AX was performed to evaluate persistence of DNA damage following simultaneous or sequential exposure. Based on CalcuSyn modeling, HDIs synergized with DNA damaging agents only when added simultaneously. An additive-to-antagonistic effect was seen with HDI pretreatment for 24 h or with addition after cisplatin or etoposide. Furthermore, pretreatment with HDIs resulted in normalization of cell cycle and reduced PARP degradation as compared with simultaneous treatment. the increase in γH2AX phosphorylation confirmed that simultaneous, but not sequential treatment enhanced double-stranded DNA breaks. these results suggest that DNA relaxation is not required for synergy of HDIs with DNA damaging agents and that scheduling of drug administration will be critical for rational development of clinical protocols.

Original languageEnglish (US)
Pages (from-to)3119-3128
Number of pages10
JournalCell Cycle
Volume10
Issue number18
DOIs
StatePublished - Sep 15 2011
Externally publishedYes

Keywords

  • Combination index
  • Drug interaction
  • PARP degradation
  • Synergy
  • dsDNA break
  • γH2AX phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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