p53 gene status and chemosensitivity of childhood acute lymphoblastic leukemia cells to adriamycin

Lam, Viengthong; McPherson, J. Peter; Salmena, Leonardo; Lees, Jodi; Chu, William; Sexsmith, Elizabeth; Hedley, David W.; Freedman, Melvin H.; Reed, John C.; Malkin, David; Goldenberg, Gerald J.

doi:10.1016/s0145-2126(99)00102-2

Cited by 31 publications

(14 citation statements)

References 40 publications

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“…However, resistance to apoptosis severely limits the e cacy of many anti-cancer drugs, including certain types of tumors that do not respond to the cytotoxic e ect of VP16 and doxorubicin (Dingemans et al, 1999;Long et al, 1991). These tumors exhibit various alterations in their genetic repertoir of growth control and apoptosis, including the functional loss of p53 (Lam et al, 1999) and mutations in the topoIIa gene (Dingemans et al, 1999;Mao et al, 1999). Another mechanism by which tumor cells may have gained resistance to cytotoxic drugs includes the activation of NF-kB (Jeremias et al, 1998;McDade et al, 1999), a condition that has been recently reported for some pancreatic carcinoma cells (Wang et al, 1999a).…”

Section: Introductionmentioning

confidence: 97%

Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

et al. 2001

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The transcription factor NF-kB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that di er in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 mM) and doxorubicin (0.3 mM): Highly sensitive BxPC-3 and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kB activity in all cell lines, whereas basal NF-kB binding was nearly undetectable in BxPc-3 and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkBa super-repressor, strongly enhanced the apoptotic e ects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kB activity rather than the transient induction of NF-kB by some anti-cancer drugs. Blockade of basal NF-kB activity by well established drugs e ciently reduces chemoresistance of pancreatic cancer cells and o ers the potential for improved therapeutic strategies. Oncogene (2001) 20, 859 ± 868.

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Section: Introductionmentioning

confidence: 97%

Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

et al. 2001

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“…Moreover, reduced BAX expression is also associated with a poor response to combination chemotherapy in women with metastatic breast cancer and correlates with shorter overall survival in solid tumors [7,8]. Overexpression of BAX has been shown to promote apoptosis and increase the sensitivity of cancer cells to a variety of antineoplastic agents [26]. Tsuruta et al [27] also used 10 µM cis-DDP and reported that this compound increased the BAX level in cis-DDP sensitive human ovarian cancer cell line A2780 and the induced level of this gene was low in the more cis-DDP resistant lines.…”

Section: Discussionmentioning

confidence: 99%

Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP

et al. 2005

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Lung cancer remains one of the most common causes of cancer-related death worldwide. Approximately 80% is histologically non-small cell lung carcinoma (NSCLC) and in about 70% of patients it is an unresectable type. Clinical studies indicated that application of platinum derivatives caused good results and combinations of platinum with other agents could improve median survivals. In view of the central problem of sufficient efficiency of drugs in chemotherapy, efforts have focused on the development of alternative platinum-based analogues that can be more effective in cancer treatment. cis-bis(3-aminoflavone)dichloroplatinum(II) (cis-Pt(II) complex of 3-aminoflavone) represents a novel class of platinum-based potential antitumour agents. In order to evaluate the degree of apoptosis, acridine orange/ethidium bromide and Hoechst 33258/propidum iodide double staining as well as RT-PCR (P53 and BAX expression evaluation) were used in lung cancer cell line A549 after treatment with this compound in comparison with cis-diamminedichloroplatinum(II) (cis-DDP). Apoptotic cells at early and late stages and also necrotic ones were observed after usage of cis-Pt(II) complex of 3-aminoflavone and the percentage of these cells outnumbered the values obtained after cis-DDP application. The former compound induced a higher percentage of P53 and BAX expression in A549 cells in comparison with the latter one. Results indicate the beneficial properties of cis-Pt(II) complex of 3-aminoflavone as a potential antitumor drug.

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“…Most chemotherapeutic agents used in ALL treatment, including glucocorticoids, vincristine and doxorubicin, induce cell growth inhibition and apoptosis that are linked to p53 function. [35][36][37] Particularly, doxorubicin-induced cell death has been well characterized as occurring through DNA damage and induction of p53-dependent apoptosis. 38 It has been reported that overexpression of MDM2 by leukemic cells from childhood ALL patients was associated with early treatment failure.…”

Section: Nutlin-3 Induces Apoptosis In All Cellsmentioning

confidence: 99%

MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2

et al. 2008

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In pediatric acute lymphoblastic leukemia (ALL), overexpression of murine double minute 2 (MDM2) protein by leukemic cells is typically associated with a wild-type (wt)-p53 phenotype and chemoresistance. A recently developed small-molecule antagonist of MDM2, nutlin-3, inhibits the MDM2-p53 interaction, resulting in induction of p53 activity and apoptosis. In this study, we evaluated the cytotoxic effect of nutlin-3 on ALL cells with different p53 status and MDM2 expression, using 18 cell lines and 30 primary leukemia samples. We found that both ALL cell lines and primary ALL samples with wt-p53 are sensitive to nutlin-3. No cytotoxic effect of nutlin-3 was detected in ALL cells with either p53-mutant or -null phenotype. In wt-p53 ALL cells, there was a significant positive correlation between MDM2 expression levels and sensitivity to nutlin-3. Nutlin-3-induced cell death was mediated by p53-induced activation of proapoptotic proteins and by p53-induced repression of the anti-apoptotic protein survivin. As p53 function is inhibited by MDM2 in chemoresistant, MDM2-overexpressing ALL cells, potent killing of these cells by nutlin-3 suggests that this agent may be a novel therapeutic for refractory ALL.

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p53 gene status and chemosensitivity of childhood acute lymphoblastic leukemia cells to adriamycin

Cited by 31 publications

References 40 publications

Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP

MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2

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