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

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Blank Nitric oxide-donating acetylsalicylic acid induces apoptosis in chronic

lymphocytic leukemia cells and shows strong anti-tumor efficacy in vivo.

R Razavi, I Gehrke, RK Gandhirajan, SJ Poll-Wolbeck, M Hallek, and KA Kreuzer

Clin. Cancer Res., November 19, 2010; .

Department I of Internal Medicine, University of Cologne.

PURPOSE: Nitric oxide-donating acetylsalicylic acid (NO-ASA) has been shown to

possess an anti-neoplastic effect in Wnt/?-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/PI-staining

and immunoblotting of caspases, PARP, and anti-apoptotic proteins. Interference

of NO-ASA with Wnt/?-catenin-signaling was analysed 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 which were treated with 100

mg para-NO-ASA/kg body weight p.o. for 21 days.RESULTS: para-NO-ASA induced

apoptosis in CLL-cells with a LC50 of 8.72 ?M + 0.04 ?M, while healthy blood

cells were not affected. Further, the compound induced caspase 9, 3 and PARP

cleavage. Additionally, cleavage of ?-catenin and downregulation of

?-catenin/Lef-1 targets was observed. para-NO-ASA demonstrated strong anti-tumor

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.

PMID: 21097689