17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis

Turgut, Burhan; Vural, Özden; Pala, Funda Sibel; Pamuk, Gülsüm Emel; Tabakçıoğlu, Kıymet; Demir, Muzaffer; Öngören, Şeniz; Soysal, Teoman; Algüneş, Cetin

doi:10.1080/10428190601059829

Cited by 34 publications

(22 citation statements)

References 42 publications

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“…There was a trend to higher resistance to fludarabine in del(17p) cases [consistent with Turgut et al (27)] and to both drugs for the types A and B p53 dysfunctional samples, in line with Sturm et al (28), who found increased resistance to fludarabine and chlorambucil in cases with p53 mutations.…”

Section: Discussionsupporting

confidence: 77%

DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia

Willmore

Elliott²,

Mainou‐Fowler³

et al. 2008

Clinical Cancer Research

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Purpose: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL. Experimental Design: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNAPKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of gH2AX). Results: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser 2056. High DNA-PK levels predicted for reduced treatment-free interval. Conclusions: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.

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Section: Discussionsupporting

confidence: 77%

DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia

Willmore

Elliott²,

Mainou‐Fowler³

et al. 2008

Clinical Cancer Research

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“…4B). Del17p results in loss of expression of p53 and is associated with short survival time and resistance to purine analogues, such as fludarabine (30,31). The three samples with del17p were assessed for fludarabine-and PBOX-15-induced apoptosis after 24 hour treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

et al. 2009

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Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC 50 of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV H genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH 2 -terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV H and ZAP-70 −

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“…[2][3][4][5] Therefore, new agents capable of effectively killing p53-null CLL cells would have significant clinical impact. Among 30 CLL samples tested for genetic abnormalities, 7 samples had deletion of 17p.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 In particular, CLL cells with unfavorable cytogenetic alterations such as deletion of chromosome 17p with loss of p53 are often resistant to fludarabine and cyclophosphamide. 4,5 Similarly, CLL cells from patients in advanced disease stages or with a history of prior chemotherapy exhibit elevated oxidative stress, 6 and thus may have a greater potential to acquire additional mutations and genetic abnormalities, leading to drug resistance and disease progression. This presents a significant challenge in treatment of CLL.…”

Section: Introductionmentioning

confidence: 99%

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Trachootham

Zhang

et al. 2008

Blood

180

179

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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n ‫؍‬ 58) and healthy subjects (n ‫؍‬ 12), we showed that both fludarabineresistant and -sensitive CLL cells were highly sensitive to ␤-phenylethyl isothiocyanate (PEITC) with mean IC 50 values of 5.4 M and 5.1 M, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC 50 ‫؍‬ 27 M, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation.

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17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis

Cited by 34 publications

References 42 publications

DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia

DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

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