Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis.
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.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
Jin
J
Li
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
Eric R
ER
Falcone
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States.
Sarah A
SA
Holstein
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
Amy C
AC
Anderson
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
Dennis L
DL
Wright
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States; Institute for Systems Genomics, University of Connecticut, Storrs, CT, United States. Electronic address: andrew.wiemer@uconn.edu.
Andrew J
AJ
Wiemer
D000107:Acetylation / Q000187:drug effects; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D039821:Monoterpenes / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014334:Tropolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D006657:Histones; D039821:Monoterpenes; D016159:Tumor Suppressor Protein p53; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014334:Tropolone; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; C009479:beta-thujaplicin
Apoptosis; Iron; Leukemia; Tropolone; Vorinostat; Vorinostat (PubChem CID: 5311); alpha-naphthyl tropolone (PubChem CID: 72163687)
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