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Nitric oxide-donating acetylsalicylic acid induces apoptosis in chronic lymphocytic leukemia cells and shows strong antitumor efficacy in vivo.

AbstractPURPOSE:
Nitric oxide-donating acetylsalicylic acid (NO-ASA) has been shown to possess an antineoplastic effect in Wnt-/β-catenin-active cancers. As chronic lymphocytic leukemia (CLL) cells exhibit aberrantly active Wnt signaling, we investigated the effect of the para-isomer of NO-ASA on CLL cell survival in vitro and in a CLL-like xenograft mouse model.
EXPERIMENTAL DESIGN:
Apoptosis in primary CLL cells was determined by flow cytometric annexin V-FITC (fluorescein isothiocyanate)/PI (propidium iodide) staining and immunoblotting of caspases, poly(ADP-ribose) polymerase (PARP), and antiapoptotic proteins. Interference of NO-ASA with Wnt/β-catenin signaling was analyzed through immunoblots of different pathway members. Influence of caspase activation was investigated by pretreatment with a pan-caspase inhibitor. CLL-like JVM3 cells were subcutaneously inoculated into irradiated nude mice that were treated with 100 mg of para-NO-ASA/kg of body weight p.o. (by mouth) for 21 days.
RESULTS:
para-NO-ASA induced apoptosis in CLL cells with an LC(50) (lethal concentration) of 8.72 + 0.04 μmol/L, whereas healthy blood cells were not affected. Furthermore, the compound induced caspase 9, caspase 3, and PARP cleavage. In addition, cleavage of β-catenin and downregulation of β-catenin/lymphoid enhancer factor (Lef)-1 targets was observed. para-NO-ASA demonstrated strong antitumor efficacy in the xenograft mouse model with a tumor inhibtion rate of 83.4%. During therapy, no gross toxicity could be observed.
CONCLUSIONS:
para-NO-ASA selectively induces apoptosis in primary CLL cells and efficiently reduces tumor growth in a CLL-like xenograft model. As NO-ASA is orally available and is generally well tolerated, para-NO-ASA might be a promising new compound for CLL therapy.
AuthorsRegina Razavi, Iris Gehrke, Rajesh Kumar Gandhirajan, Simon Jonas Poll-Wolbeck, Michael Hallek, Karl-Anton Kreuzer
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 2 Pg. 286-93 (Jan 15 2011) ISSN: 1557-3265 [Electronic] United States
PMID21097689 (Publication Type: Journal Article)
Copyright©2010 AACR.
Chemical References
  • Antineoplastic Agents
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Nitric Oxide Donors
  • beta Catenin
  • Caspases
  • Aspirin
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Aspirin (therapeutic use)
  • Caspases (biosynthesis)
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
  • Lymphoid Enhancer-Binding Factor 1 (metabolism)
  • Mice
  • Mice, Nude
  • Nitric Oxide Donors (therapeutic use)
  • Xenograft Model Antitumor Assays
  • beta Catenin (metabolism)

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