nitrophenols and fludarabine

Quercetin is a flavonoid, of the subclass flavonols, possessing potential anticancer properties. It has often been defined as a functionally pleiotropic molecule because it can simultaneously target multiple pathways bypassing or ameliorating the onset of drug resistance in malignant cells. In this context, we reviewed the sometimes paradoxical antioxidant properties of quercetin and the functional role of its glucuronide and/or sulfate conjugates to discuss the low bioavailability of the molecule measured in vivo. We recently demonstrated that quercetin is able to sensitize several leukemia cell lines as well as B cells isolated from patients affected by chronic lymphocytic leukemia (CLL) to death ligand agonists (anti-CD95 and rTRAIL). The flavonol also potentiates the effect of canonical and innovative chemotherapeutic drugs (fludarabine and ABT-737) against CLL. The apoptosis-enhancing activity of quercetin in cell lines and B-CLL cells depends upon the modulated expression and activity of Mcl-1, an anti-apoptotic protein belonging to the Bcl-2 family. Herein, we suggest that the pleotropic activity of quercetin in CLL is obtained by the direct inhibition of key protein kinases, which positively regulate Mcl-1 activity and by indirect downregulation of Mcl-1 mRNA and protein levels acting on its mRNA stability and proteasome-mediated degradation. Finally, we highlighted the pros and cons of quercetin supplementation in cancer therapy and in prevention.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrophenols; Phytochemicals; Piperazines; Protein Kinase Inhibitors; Quercetin; Sulfonamides; Vidarabine

Topics: Antineoplastic Agents; B-Lymphocytes; bcl-X Protein; Bendamustine Hydrochloride; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; CD40 Ligand; Cell Hypoxia; Cells, Cultured; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Nitrogen Mustard Compounds; Nitrophenols; Oxygen; p38 Mitogen-Activated Protein Kinases; Piperazines; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Vidarabine

Chronic lymphocytic leukemia (CLL) cells in lymph nodes (LN), from which relapses are postulated to originate, display an antiapoptotic profile in contrast to CLL cells from peripheral blood (PB). The BH3 mimetic ABT-737 antagonizes the antiapoptotic proteins Bcl-X(L) and Bcl-2 but not Mcl-1 or Bfl-1. Previously, it was shown that CD40-stimulated CLL cells were resistant to ABT-737. We aimed to define which antiapoptotic proteins determine resistance to ABT-737 in CLL and whether combination of known antileukemia drugs and ABT-737 was able to induce apoptosis of CD40-stimulated CLL cells.. To mimic the LN microenvironment, PB lymphocytes of CLL patients were cultured on feeder cells expressing CD40L and treated with ABT-737 with or without various drugs. In addition, we carried out overexpression or knockdown of pro- and antiapoptotic proteins in immortalized primary B cells.. Upon CD40 stimulation patient-specific variations in ABT-737 sensitivity correlated with differences in levels of Mcl-1 and its antagonist Noxa. Knockdown of Noxa, as well as Mcl-1 overexpression, corroborated the importance of the Noxa/Mcl-1 ratio in determining the response to ABT-737. Inhibition of NF-κB resulted in increased Noxa levels and enhanced sensitivity to ABT-737. Interestingly, increasing the Noxa/Mcl-1 ratio, by decreasing Mcl-1 (dasatinib and roscovitine) or increasing Noxa levels (fludarabine and bortezomib), resulted in synergy with ABT-737.. Thus, the Noxa/Mcl-1 balance determines sensitivity to ABT-737 in CD40-stimulated CLL cells. These data provide a rationale to investigate the combination of drugs which enhance the Noxa/Mcl-1 balance with ABT-737 to eradicate CLL in chemoresistant niches.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Biphenyl Compounds; CD40 Antigens; CD40 Ligand; Coculture Techniques; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Mice; Middle Aged; Minor Histocompatibility Antigens; Myeloid Cell Leukemia Sequence 1 Protein; NF-kappa B; NIH 3T3 Cells; Nitrophenols; p38 Mitogen-Activated Protein Kinases; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Signal Transduction; Sulfonamides; Thiazoles; Tumor Cells, Cultured; Vidarabine

The in vitro effects of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR, fenretinide) on primary B-cell chronic lymphocytic leukemia (CLL) cells from previously untreated CLL patients were investigated. 4HPR promoted the intrinsic apoptotic pathway by reactive oxygen species (ROS) generation and was accompanied by drop of Mcl-1 protein expression. The latter was not attributable to transcriptional downregulation but to protein degradation mediated by jun N-terminal kinase activation, and likely by NF-kB downregulation and Noxa upregulation. CLL cells stimulated in vitro with CD40L did not increase 4HPR chemoresistance if activation was accompanied by proliferation. Intra-patient analysis confirmed that the proliferating pool of CLL cells was more sensitive to the cytotoxic action of 4HPR than the activated but resting CLL subpopulation. The different 4HPR susceptibility of the two subpopulations was associated with higher Noxa expression in proliferating CLLs. Combination experiments revealed that 4HPR strongly potentiated ABT-737 cytotoxicity, especially in proliferating CLL cells that displayed amplified chemoresistance to ABT-737 alone. Synergic cytotoxicity was also demonstrated in combination with fludarabine, in both resting and stimulated CLL samples. This study entitles 4HPR to be assayed as a chemotherapeutic adjuvant for the treatment of CLL.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Proliferation; Drug Synergism; Fenretinide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sulfonamides; Vidarabine

As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLX(L). In the present work, we report that ABT-737 is highly effective (LC(50)<50 nM) as a single agent against most (21/30) primary CLL samples, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL samples to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 samples least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; bcl-X Protein; Biphenyl Compounds; Dexamethasone; Doxorubicin; Drug Synergism; Etoposide; Humans; In Vitro Techniques; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Mimicry; Nitrophenols; Piperazines; Prognosis; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Vidarabine