Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Jin Li, Eric R. Falcone, Sarah A Holstein, Amy C. Anderson, Dennis L. Wright, Andrew J. Wiemer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Tropolones, such as β-thujaplicin, are small lead-like natural products that possess a variety of biological activities. While the β-substituted natural products and their synthetic analogs are potent inhibitors of human cancer cell growth, less is known about their α-substituted counterparts. Recently, we synthesized a series of α-substituted tropolones including 2-hydroxy-7-(naphthalen-2-yl)cyclohepta-2,4,6-trien-1-one (α-naphthyl tropolone). Here, we evaluate the antiproliferative mechanisms of α-naphthyl tropolone and the related α-benzodioxinyl analog. The α-substituted tropolones inhibit growth of lymphocytic leukemia cells, but not healthy blood cells, with nanomolar potency. Treatment of leukemia cell lines with the tropolone dose-dependently induces apoptosis as judged by staining with annexin V and propidium iodide and Western blot analysis of cleaved caspase 3 and 7. Moreover, pre-treatment of cells with the caspase inhibitor Z-VAD-FMK inhibited the apoptotic effects of the tropolone in two lymphocytic lines. Caspase inhibition also blocked elevated histone acetylation caused by the tropolone, indicating that its effects on histone acetylation are potentiated by caspases. In contrast, α-naphthyl tropolone upregulated p53 expression and phosphorylation of Akt and mTOR in a manner that was not rescued by caspase inhibition. The effects of tropolone were blocked by co-incubation with high levels of free extracellular iron but not by pre-loading with iron. Additionally, dose and time dependent reduction in ex vivo viability of cells from leukemia patients was observed. Taken together, we demonstrate that α-substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant lymphocytes.

Original languageEnglish (US)
Pages (from-to)438-448
Number of pages11
JournalPharmacological Research
Volume113
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Tropolone
Caspases
Leukemia
Apoptosis
Acetylation
Biological Products
Histones
Iron
Trientine
Caspase 7
Lymphoid Leukemia
Caspase Inhibitors
Propidium
Annexin A5
Growth
Caspase 3
DNA Repair
DNA Damage

Keywords

  • Apoptosis
  • Iron
  • Leukemia
  • Tropolone
  • Vorinostat

ASJC Scopus subject areas

  • Pharmacology

Cite this

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis. / Li, Jin; Falcone, Eric R.; Holstein, Sarah A; Anderson, Amy C.; Wright, Dennis L.; Wiemer, Andrew J.

In: Pharmacological Research, Vol. 113, 01.11.2016, p. 438-448.

Research output: Contribution to journalArticle

Li, Jin ; Falcone, Eric R. ; Holstein, Sarah A ; Anderson, Amy C. ; Wright, Dennis L. ; Wiemer, Andrew J. / Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis. In: Pharmacological Research. 2016 ; Vol. 113. pp. 438-448.
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