Small-Molecule Inhibitor Which Reactivates p53 in Human T-Cell Leukemia Virus Type 1-Transformed Cells

Jung, Kwang Yoon; Dasgupta, Arindam; Huang, Keven; Jeong, Soo‐Jin; Pise-Masison, Cynthia A.; Gurova, Katerina V.; Brady, John

doi:10.1128/jvi.00690-08

Cited by 24 publications

(28 citation statements)

References 51 publications

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“…[52][53][54] In our study Nutlin-3a caused rapid apoptosis in a number of ATL-related cell lines with wild-type p53, and typical targets of p53, such as BAX, NOXA, PUMA, DR5 and survivin, actually responded to Nutlin-3a treatment. These results indicate that Nutlin-3a can overcome Tax-induced p53 impairment even in cells with high Tax expression.…”

Section: Discussionmentioning

confidence: 54%

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

et al. 2009

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It has been reported that the induction of cellular senescence through p53 activation is an effective strategy in tumor regression. Unfortunately, however, tumors including adult T-cell leukemia/lymphoma (ATL) have disadvantages such as p53 mutations and a lack of p16INK4a and/or p14 ARF. In this study we characterized Nutlin-3a-induced cell death in 16 leukemia/ lymphoma cell lines. Eight cell lines, including six ATL-related cell lines, had wild-type p53 and Nutlin-3a-activated p53, and the cell lines underwent apoptosis or cell-cycle arrest, whereas eight cell lines with mutated p53 were resistant. Interestingly, senescence-associated-b-galactosidase (SA-b-gal) staining revealed that only ATL-related cell lines with wild-type p53 showed cellular senescence, although they lack both p16 . Furthermore, knockdown of Tp53-induced glycolysis and apoptosis regulator (TIGAR), a novel target gene of p53, by small interfering RNA(siRNA) indicated its important role in the induction of cellular senescence. As many patients with ATL carry wild-type p53, our study suggests that p53 activation by Nutlin-3a is a promising strategy in ATL. We also found synergism with a combination of Nutlin-3a and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), suggesting the application of Nutlin-3a-based therapy to be broader than expected.

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Section: Discussionmentioning

confidence: 54%

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

et al. 2009

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“…In this study, we demonstrated that 9AA also inhibits the PI3K/AKT/mTOR signaling pathway, a property that is expected to contribute to the anticancer effect of the compound. Inhibition of AKT activity by 9AA was recently confirmed in a report from our collaborators on a model of human T-cell leukemia virus-transformed cells (Jung et al, 2008). The unique ability of 9AA to modulate multiple pathways that are deregulated in tumor cells in the desired direction further strengthens the prospect of using molecules similar to 9AA as anticancer agents.…”

Section: Small Molecule Targeting Akt/mtor Pi3k Nf-jb and P53 Pathwmentioning

confidence: 74%

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-jB (NF-jB) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of twodimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110c. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/ mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110c translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, thereby impacting the p53 and NF-jB pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-jB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells.

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“…In contrast, chemotherapeutic agents that cause DNA breaks are known to activate NF-κB in tumor cells through ATM-mediated phosphorylation of IκB kinase γ (IKKγ) (37–39). Because NF-κB negatively regulates p53 (6, 7, 33, 34, 36), activation of NF-κB by these drugs works against effective activation of p53 and thereby reduces their overall anticancer effect (Fig. 8B).…”

Section: Discussionmentioning

confidence: 99%

Curaxins: Anticancer Compounds That Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT

et al. 2011

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Effective eradication of cancer requires treatment directed against multiple targets. The p53 and nuclear factor κB (NF-κB) pathways are dysregulated in nearly all tumors, making them attractive targets for therapeutic activation and inhibition, respectively. We have isolated and structurally optimized small molecules, curaxins, that simultaneously activate p53 and inhibit NF-κB without causing detectable genotoxicity. Curaxins demonstrated anticancer activity against all tested human tumor xenografts grown in mice. We report here that the effects of curaxins on p53 and NF-κB, as well as their toxicity to cancer cells, result from “chromatin trapping” of the FACT (facilitates chromatin transcription) complex. This FACT inaccessibility leads to phosphorylation of the p53 Ser392 by casein kinase 2 and inhibition of NF-κB–dependent transcription, which requires FACT activity at the elongation stage. These results identify FACT as a prospective anticancer target enabling simultaneous modulation of several pathways frequently dysregulated in cancer without induction of DNA damage. Curaxins have the potential to be developed into effective and safe anticancer drugs.

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Small-Molecule Inhibitor Which Reactivates p53 in Human T-Cell Leukemia Virus Type 1-Transformed Cells

Cited by 24 publications

References 51 publications

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

Curaxins: Anticancer Compounds That Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT

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