Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes

Adams, DJ; Levesque, MC; Weinberg, J. Brice; Smith, Kimberley J.; Flowers, JL; Moore, Joseph O.; Colvin, O. Michael; Silber, Robert

doi:10.1038/sj.leu.2402291

Cited by 16 publications

(9 citation statements)

References 47 publications

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“…More important is the finding that low concentrations of an NO donor can partially revert flavopiridol-elicited apoptosis. That high concentrations of the same NO donor can stimulate apoptosis and eventually potentiate the effect of flavopiridol, as already found in the case of fludarabine, 28 is not surprising because the biphasic effects of NO on apoptosis are well known. 15 From our data, it is tempting to speculate that, among other mechanisms such as inhibition of XIAP, 4 flavopiridol-induced downregulation of iNOS expression and suppression of NO release is a molecular switch contributing to subsequent caspase-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 57%

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

et al. 2003

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Flavopiridol, an inhibitor of cyclin-dependent kinases and other protein kinases, induces in vitro apoptosis of malignant cells from B-cell chronic lymphocytic leukemia (B-CLL). Previously, we reported that nitric oxide (NO), produced by an inducible NO synthase (iNOS), spontaneously expressed by the B-CLL cells, contributed to their deficiency in apoptosis. In the present work, we show that ex vivo treatment of leukemic cells from B-CLL patients with flavopiridol results in the inhibition of iNOS expression, as determined by immunofluorescence and Western blotting, and in a marked inhibition of NO production measured in situ with a specific fluorescent probe (DAF-2 DA). These effects are accompanied by membrane, mitochondrial and nuclear events of apoptosis. Flavopiridol exposure also results in the stimulation of caspase 3 activity and in caspasedependent cleavage of p27 kip1 , a negative regulator of the cell cycle, which is overexpressed in B-CLL. Thus, flavopiridol is capable of downregulating both iNOS and p27 kip1 expression in B-CLL cells. Furthermore, flavopiridol-promoted apoptosis is partly reverted by an NO donor, suggesting that inhibition of the NO pathway could participate in the apoptotic effects of flavopiridol on the leukemic cells.

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Section: Discussionmentioning

confidence: 57%

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

et al. 2003

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“…[87] Three-dimensional analysis of the combination of fludarabine and DETA-NO • showed that at the optimum combination, cell death of 80–90% should be expected. As shown in Fig.…”

Section: Nitric Oxide Therapymentioning

confidence: 99%

Nitric oxide in cancer metastasis

Cheng¹,

Wang²,

Mollica³

et al. 2014

Cancer Letters

161

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COX-2, cyclooxygenase; CXCR4, CXC chemokine receptor 4; ECM, extracellular matrix; ELAM-1, endothelial leukocyte adhesion molecule 1; eNOS, endothelial nitric oxide synthase; GC, guanylyl cyclase; HIF-1, hypoxia-inducible factor-1; HUVECs, human umbilical vascular endothelial cells; IL-33, cytokine interleukin-33; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; nNOS, neuronal nitric oxide synthase; NO•, nitric oxide; NO•-NSAIDs, nitric oxide-releasing non-steroidal anti-inflammatory drugs; NOS, nitric oxide synthase; PCNA, proliferating cell nuclear antigen; PKC, protein kinase C; QUER, quercetin; TPA, 12-O-tetradecanoylphorbol 13-acetate; t-PTER, trans-pterostilbene; VEGF-C, vascular endothelial growth factor-C

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“…Nitric oxide (NO) protects endothelial cells and cardiomyocytes from apoptosis induced by oxidative stress and doxorubicin [19][20][21][22][23][24] and increases the antitumoral activity of several agents, including doxorubicin [25], cisplatin [26], melphalan [27], fludarabine [28] and nonsteroidal antiinflammatory drugs [29,30]. In the search of a new approach to limit anthracycline cardiomyopathy, we hypothesized that a PEG conjugate of EPIbearing moieties that release NO would result in a new chemical entity (NO-PEG-EPI, named BP-747) that possesses either the advantage of drug pegylation and the cardio-protective and antitumoral properties of NO.…”

Section: Introductionmentioning

confidence: 99%

Cardiac safety and antitumoral activity of a new nitric oxide derivative of pegylated epirubicin in mice

et al. 2007

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The use of epirubicin is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte apoptosis. In a previous in-vitro study, we have provided evidence that a new formulation of pegylated epirubicin- bearing moieties that release nitric oxide, named BP-747, exerted a potent antitumoral activity against a colon cancer cell line, which was completely devoid of cytotoxic activity against cardiomyocytes. The aim of this study was to investigate the antitumoral and cardiotoxic profile of BP-747 in Caco-2 and SKOV-2 tumor-bearing mice. Epirubicin-induced cardiomyopathy was detected by clinical (survival, weight loss), anatomical (heart weight loss) and biochemical evaluations (measurement of serum troponin and creatine phosphokinase levels). The antitumoral activity was investigated by the measurement of tumor diameters and weight. In comparison with free epirubicin and pegylated epirubicin, BP-747 showed more potent antineoplastic effects, as demonstrated by the 95% reduction of tumor volume. Moreover, while administration of epirubicin and pegylated epirubicin resulted in the development of a severe anthracycline cardiomyopathy, BP-747-treated mice were virtually devoid of clinical and biochemical signs of cardiotoxicity. The present data provide evidence that addition of a nitric oxide-releasing moiety to pegylated epirubicin confers a new and unique cytotoxic profile to the drug.

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Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes

Cited by 16 publications

References 47 publications

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia

Nitric oxide in cancer metastasis

Cardiac safety and antitumoral activity of a new nitric oxide derivative of pegylated epirubicin in mice

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