Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B-cells.

We recently reported that resveratrol, a grape-derived polyphenol, in vitro induces the apoptosis of leukemic B-cells and simultaneously inhibits the production of endogenous nitric oxide (NO) through inducible NO synthase (iNOS) down-regulation. The same results were observed in the present study with not only acetate derivatives of polyphenols, particularly the pentaacetate of -viniferin (resveratrol dimer), but also with a synthetic flavone (a diaminomethoxyflavone) in both leukemia B-cell lines and B-cell chronic lymphocytic leukemia (B-CLL) patients' cells. Moreover, flavopiridol, another flavone already known for its pro-apoptotic properties in B-CLL cells, was also found to down-regulate both iNOS expression and NO production. Thus, inhibition of the NO pathway during apoptosis of leukemia B-cells appears a common mechanism for several compounds belonging to two distinct families of phytoalexins, the flavones and grape-derived polyphenols.

[1]  Jen-kun Lin,et al.  Suppression of nitric oxide synthase and the down‐regulation of the activation of NFκB in macrophages by resveratrol , 1999, British journal of pharmacology.

[2]  H. Sedlacek.  Mechanisms of action of flavopiridol. , 2001, Critical reviews in oncology/hematology.

[3]  M. Grever,et al.  Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. , 1998, Blood.

[4]  E. Sausville,et al.  Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol , 1998 .

[5]  F. Mentz,et al.  Comparative Antiproliferative and Apoptotic Effects of Resveratrol, ϵ-viniferin and Vine-shots Derived Polyphenols (Vineatrols) on Chronic B Lymphocytic Leukemia Cells and Normal Human Lymphocytes , 2002, Leukemia & lymphoma.

[6]  F. Ross,et al.  Establishment of a karyotypically normal B-chronic lymphocytic leukemia cell line; evidence of leukemic origin by immunoglobulin gene rearrangement. , 1990, Leukemia research.

[7]  B. Gaston,et al.  S-Nitrosylation of mitochondrial caspases , 2001, The Journal of cell biology.

[8]  R. Greil,et al.  Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells , 2000, Cell Death and Differentiation.

[9]  R A F MacLeod,et al.  DNA profiling and cytogenetic analysis of cell line WSU-CLL reveal cross-contamination with cell line REH (pre B-ALL) , 2002, Leukemia.

[10]  R. Mohammad,et al.  Analysis of resveratrol‐induced apoptosis in human B‐cell chronic leukaemia , 2002, British journal of haematology.

[11]  John Calvin Reed,et al.  Protein Kinase Inhibitors Flavopiridol and 7-hydroxy-staurosporine Down-regulate Antiapoptosis Proteins in B-cell Chronic Lymphocytic Leukemia , 2022 .

[12]  D. Koop,et al.  Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. , 1999, Biochemical pharmacology.

[13]  D. Geller,et al.  The role of protein phosphatases in the expression of inducible nitric oxide synthase in the rat hepatocyte , 1999, Hepatology.

[14]  J Dörrie,et al.  Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. , 2001, Cancer research.

[15]  S. Seki,et al.  Effect of antioxidants, resveratrol, quercetin, and N‐acetylcysteine, on the functions of cultured rat hepatic stellate cells and kupffer cells , 1998, Hepatology.

[16]  F. Sigaux,et al.  Expression of a functional inducible nitric oxide synthase in hairy cell leukaemia and ESKOL cell line , 2000, Leukemia.

[17]  Ko Jp.  Mechanisms involved in the pro- and anti-apoptotic role of NO in human leukemia. , 2000 .

[18]  G. Kong,et al.  Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. , 1999, Cancer letters.

[19]  M. Taylor,et al.  Characterization of a new cell line (ESKOL) resembling hairy-cell leukemia: a model for oncogene regulation and late B-cell differentiation. , 1991, Leukemia research.

[20]  F. Sigaux,et al.  B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity. , 1998, Blood.

[21]  R. Mohammad,et al.  Establishment of a human B-CLL xenograft model: utility as a preclinical therapeutic model. , 1996, Leukemia.

[22]  J. Gabrilove,et al.  The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. , 1997, Blood.

[23]  J. Reiffers,et al.  Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. , 2002, Carcinogenesis.

[24]  A. Passaniti,et al.  Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. , 2001, Carcinogenesis.

[25]  H. Matsuda,et al.  Structural requirements of flavonoids for nitric oxide production inhibitory activity and mechanism of action. , 2003, Bioorganic & medicinal chemistry.

[26]  S. Pervaiz,et al.  Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. , 1998, Blood.

[27]  Y. Pommier,et al.  Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. , 2003, Cancer research.

[28]  A. Anichini,et al.  Antiapoptotic role of endogenous nitric oxide in human melanoma cells. , 2001, Cancer research.

[29]  A. Hunter,et al.  Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an ∼700 kDa Apaf-1 containing apoptosome complex , 2001, Leukemia.

[30]  Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. , 2000, Carcinogenesis.

[31]  D. L. Wilson,et al.  IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells , 2003, Leukemia.

[32]  D. Dauzonne,et al.  Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones , 1997 .

[33]  C. Croce,et al.  Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. , 1998, Blood.

[34]  M. Nehls,et al.  Suppression of Apoptosis by Nitric Oxide via Inhibition of Interleukin-1β–converting Enzyme (ICE)-like and Cysteine Protease Protein (CPP)-32–like Proteases , 1997, The Journal of experimental medicine.

[35]  N. Janakiraman,et al.  Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging , 2000, Bone Marrow Transplantation.

[36]  M. Tsan,et al.  Anti-leukemia Effect of Resveratrol , 2002, Leukemia & lymphoma.

[37]  S. Mariotto,et al.  Rapid Inactivation of NOS-I by Lipopolysaccharide Plus Interferon-γ-induced Tyrosine Phosphorylation* , 1999, The Journal of Biological Chemistry.

[38]  T. Billiar,et al.  Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. , 1997, Biochemical and biophysical research communications.

[39]  E. Mekada,et al.  Characterization of Rat TOM40, a Central Component of the Preprotein Translocase of the Mitochondrial Outer Membrane* , 2000, The Journal of Biological Chemistry.

[40]  A. Shah,et al.  Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. , 2000, Biochemical pharmacology.

[41]  P. Groundwater,et al.  Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases. , 1992, Anti-cancer drug design.

[42]  A. Senderowicz.  Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies , 2001, Leukemia.

[43]  R. Greil,et al.  Resveratrol, a tumor‐suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl‐2 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  C. Fegan,et al.  Flavopiridol circumvents Bcl‐2 family mediated inhibition of apoptosis and drug resistance in B‐cell chronic lymphocytic leukaemia , 2001, British journal of haematology.

[45]  B. Bauvois,et al.  Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. , 2003, Journal of medicinal chemistry.

[46]  Daniel Schwartz,et al.  Methodes Statistiques a L'Usage des Medecins et des Biologistes , 1964 .

[47]  C. Reutelingsperger,et al.  Expression on B Cells Undergoing Apoptosis Annexin V for Flow Cytometric Detection of Phosphatidylserine , 2022 .

[48]  Weiya Ma,et al.  Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. , 1999, Carcinogenesis.