γ-Secretase inhibitors suppress the growth of leukemia and lymphoma cells

Kogoshi, Hanae; Sato, Taku; Koyama, Takatoshi; Nara, Nobuo; Tohda, Shuji

doi:10.3892/or.18.1.77

Cited by 23 publications

(31 citation statements)

References 14 publications

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“…on May 9, 2018. by guest www.bloodjournal.org From but it has been shown that ␥-secretase inhibitors may be useful for the treatment of hematologic malignancies other than T-ALL. 46 Although the mechanism behind the cytotoxic effects of ␥-secretase inhibitors remains to be clarified, it has been proposed that Notch1 signaling confers chemoresistance by inhibiting p53 pathway through mTOR-dependent PI3K-Akt/ PKB pathway. 41 In considering the potential cytotoxic activity of the combination of Nutlin-3 plus ␥-secretase inhibitors toward normal tissues, previous studies have shown that Nutlin-3 is much less toxic against normal tissues with respect to neoplastic cells, 2 and might even protect normal cells from apoptosis induced by mitotic inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Secchiero

Melloni

Iasio

et al. 2009

Blood

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The small molecule inhibitor of the MDM2/ p53 interaction Nutlin-3 significantly upregulated the steady-state mRNA and protein levels of Notch1 in TP53 wild-type (OCI, SKW6.4) but not in TP53 deleted (HL-60) or TP53 mutated (BJAB) leukemic cell lines. A direct demonstration that NOTCH1 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53. Moreover, inhibition of Notch1 expression using Notch1-specific siRNA significantly increased cytotoxicity in TP53 wild-type leukemic cells. IntroductionThe activation of p53 is tightly regulated by the human homolog of murine double minute 2 (MDM2) gene, 1 which is an E3 ubiquitin ligase for p53 and itself and controls p53 half-life mainly via ubiquitindependent degradation. In response to a variety of stimuli, such as cellular stress, the p53-MDM2 interaction is disrupted and p53 rapidly accumulates within the cell. 1 Potent and selective small molecule inhibitors of the p53-MDM2 interaction, the Nutlins, have been recently reported. 2,3 These compounds bind MDM2 in the p53 binding pocket with high selectivity and can release p53 from negative control, leading to effective stabilization of p53 and activation of the p53 pathway. 2,3 It has been demonstrated that treatment with the active enantiomer Nutlin-3a results in rising levels of p53 protein and subsequent induction of cell cycle arrest and apoptosis in a variety of tumor cells. 2 In contrast to most solid tumors, TP53 is mutated in approximately 10% to 15% of both myeloid and lymphoid leukemias at diagnosis, 4 and several recent studies have demonstrated that Nutlin-3 induces ex vivo cytotoxic cell death of most TP53 wild-type primary hematologic malignancies, including acute myeloid leukemias, multiple myeloma, B-chronic lymphocytic leukemias (B-CLL), and B-cell lymphomas. [5][6][7][8][9][10][11][12][13][14][15] Although it is well established that p53 mediates a variety of cellular functions, such as cell cycle arrest, cellular senescence, and, only as ultimate choice, apoptosis, 16,17 some experimental evidence suggests that inhibition of the transcriptional activity of p53 might paradoxically result in an increase of the p53-mediated proapoptotic activity, 18 also in B-CLL cells. 19 Therefore, the aim of this study was to further investigate the relationship between the transcriptional and cytotoxic activities induced by Nutlin-3 and to elucidate whether Nutlin-3 promotes the transcription of antiapoptotic genes in leukemic cells, which might hamper and/or reduce its potential therapeutic efficacy. In this respect, it has recently emerged that a potential target gene of the p53 pathway is NOTCH1, 20 which belongs to an evolutionarily conserved pathway that profoundly impacts mammalian development. Of note, a recent study published while this article was under preparation has demonstrated that circulating B-CLL cells overexpress Notch1 and Notch2 family members with respect to circulating normal B lymphocytes. 21 The same study suggested that constitutively...

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Section: Discussionmentioning

confidence: 99%

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Secchiero

Melloni

Iasio

et al. 2009

Blood

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“…When EBNA2-ER is activated in P493-6 cells by estradiol, EBNA2 direct activation of Notch target genes would not require ligand-activated Notch, and hence EBNA2-ER-driven P493-6 cells would be resistant to γ-secretase inhibitors, as we have documented. A recent study reports that selected B-cell lines are sensitive to the GSIs, suggesting a therapeutic role for GSIs in B lymphoid malignancies (20). Interestingly, Jagged2 levels are increased in samples from multiple myeloma patients (8), which often have Myc overexpression (8,11).…”

Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

“…These findings suggest that JAG2 is necessary for maximal P493-6 cell proliferation in vitro. Previous studies have shown that inhibition of the γ-secretase Presenillin-1 reduces the production of the Notch intracellular domain, and subsequent downstream signaling, often resulting in apoptosis (20). To further study JAG2 loss-of-function in vitro and in vivo, we used the γ-secretase inhibitor (GSI) DAPT, which blocks Notch signaling by preventing the processing of the Notch1 receptor to form N ICD , but not the levels of Myc expression.…”

Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

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“…Cells were treated with 7.5 μmol/L LLNle or DAPT or vehicle alone (DMSO 0.1%), unless otherwise indicated, and kept in a humidified 5% CO 2 atmosphere at 37°C for the indicated time period. This concentration is in the low range reported by several previous in vitro studies (38,(74)(75)(76)(77). The γ-secretase inhibitor L-685,458 and the proteasome inhibitor lactacystin were obtained from SigmaAldrich, dissolved at 10 mmol/L in DMSO and 30 mmol/L in H 2 O, respectively, aliquoted, and stored in the dark at −20°C.…”

Section: Cell Culturementioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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γ-Secretase inhibitors suppress the growth of leukemia and lymphoma cells

Cited by 23 publications

References 14 publications

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

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