NO-donating aspirin inhibits the growth of leukemic Jurkat cells and modulates β-catenin expression

Nath, Niharika; Labaze, Georges; Rigas, Basil; Kashfi, Khosrow

doi:10.1016/j.bbrc.2004.11.009

Cited by 30 publications

(26 citation statements)

References 17 publications

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“…Previous studies have speculated that this NO/Wnt crosstalk plays a role in colon cancer, leukemia, and colitis (Williams et al, 2003;Nath et al, 2005;Wang et al, 2009). In contrast to our findings, these reports put forward the hypothesis that NO downregulates CatnB and iNOS.…”

Section: Discussioncontrasting

confidence: 99%

NO/beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation

Ding

Keller

Martinez

et al. 2012

Journal of Cell Science

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SummaryNitric oxide (NO) has been shown to play a crucial role in bone formation in vivo. We sought to determine the temporal effect of NO on murine embryonic stem cells (ESCs) under culture conditions that promote osteogenesis. Expression profiles of NO pathway members and osteoblast-specific markers were analyzed using appropriate assays. We found that NO was supportive of osteogenesis specifically during an early phase of in vitro development (days 3-5). Furthermore, ESCs stably overexpressing the inducible NO synthase showed accelerated and enhanced osteogenesis in vitro and in bone explant cultures. To determine the role of NO in early lineage commitment, a stage in ESC differentiation equivalent to primitive streak formation in vivo, ESCs were transfected with a T-brachyury-GFP reporter. Expression levels of T-brachyury and one of its upstream regulators, b-catenin, the major effector in the canonical Wnt pathway, were responsive to NO levels in differentiating primitive streak-like cells. Our results indicate that NO may be involved in early differentiation through regulation of b-catenin and T-brachyury, controlling the specification of primitive-streak-like cells, which may continue through differentiation to later become osteoblasts.

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Section: Discussioncontrasting

confidence: 99%

NO/beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation

Ding

Keller

Martinez

et al. 2012

Journal of Cell Science

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“…Numerous evidences revealed strong antineoplastic properties of NSAIDs modified by covalent attachment of NO (6,8,9,12,30). In this study, we showed for the first time that chemical modification of parental isoxazole acetic acid derivative VGX-1027 created a qualitatively new NOdonating compound possessed strong antitumor potential.…”

Section: Discussionmentioning

confidence: 65%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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Preclinical studies have shown that nitric oxide (NO) -donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NOdeprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatinresistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.

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“…With this background, it is especially interesting that this sample was highly sensitive toward para-NO-ASA with an LC 50 value of 6.31 mmol/L that is below the average LC 50 value of all tested samples (8.72 AE 0.04 mmol/L). An interesting fact is that other cancers that respond to NO-ASA treatment are known to exhibit an aberrantly active b-catenin/Tcf/Lef-1 complex, such as colon cancer (22), pancreatic cancer (29), or leukemic Jurkat cells (23). Studies in these neoplasias frequently showed reduced transcriptional activity of the b-catenin/Tcf/Lef-1 complex after NO-ASA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The same group demonstrated a disruption of the b-catenin/Tcf/ Lef-1 complex as a potential mechanism of NO-ASA action in colon cancer (13,22), a tumor where 100% of cases show an aberrant activation of Wnt/b-catenin/Tcf/Lef-1 signaling due to an APC or a CTNNB1 (b-catenin) mutation. Also, in the human T-cell leukemia cell line Jurkat, the para-isomer of NO-ASA was shown to modulate the expression of b-catenin, going along with a strong induction of apoptosis (23). In addition, in a b-catenin/Tcf/Lef-1-positive breast cancer cell line, NO-ASA was shown to exhibit potent proapoptotic abilities associated with an interference with the b-catenin/Tcf/Lef-1 complex (14).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide–Donating Acetylsalicylic Acid Induces Apoptosis in Chronic Lymphocytic Leukemia Cells and Shows Strong Antitumor Efficacy In vivo

Razavi¹,

Gehrke²,

Gandhirajan³

et al. 2011

Clinical Cancer Research

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Purpose: Nitric oxide-donating acetylsalicylic acid (NO-ASA) has been shown to possess an antineoplastic effect in Wnt-/b-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/ b-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 þ 0.04 mmol/L, whereas healthy blood cells were not affected. Furthermore, the compound induced caspase 9, caspase 3, and PARP cleavage. In addition, cleavage of b-catenin and downregulation of b-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 growthin a CLL-likexenograftmodel. As NO-ASA is orally available and is generally welltolerated, para-NO-ASA might be a promising new compound for CLL therapy. Clin Cancer Res; 17(2); 286-93. Ó2010 AACR.

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NO-donating aspirin inhibits the growth of leukemic Jurkat cells and modulates β-catenin expression

Cited by 30 publications

References 17 publications

NO/beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation

NO/beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Nitric Oxide–Donating Acetylsalicylic Acid Induces Apoptosis in Chronic Lymphocytic Leukemia Cells and Shows Strong Antitumor Efficacy In vivo

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