Selective Pharmacologic Activation of the p53-Dependent Pathway as a Therapeutic Strategy for Hematologic Malignancies

Stühmer, Thorsten; Bargou, Ralf C.

doi:10.4161/cc.5.1.2281

Cited by 16 publications

(15 citation statements)

References 24 publications

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“…This may help overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Some other recent studies have also combined Nutlin-3 with chemotherapeutic agents and seen potentiation of activity of these chemotherapeutics in vitro, in acute myelogenous leukemia, 18,19 multiple myeloma 20,21 and chronic lymphocytic leukemia, 22,23 thereby suggesting potential of Nutlin-3 in combination therapy as well.…”

Section: Nutlin-3 Downregulates Nfκb Pathwaymentioning

confidence: 92%

Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Dey

Wong²,

Bist³

et al. 2007

Cell Cycle

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Nutlins were identified as the first potent and specific small molecule Mdm2 antagonists that inhibit the p53-Mdm2 interaction. We show in this study that Nutlin-3 can downregulate TNFa induced activation of the NFκB reporter in lung cancer cells. Activation of p53 dependent transcription is not compromised when Nutlin-3 is combined with TNFa. Instead, this combination treatment decreases cell viability in a p53 dependent manner. We show that Nutlin-3 strikingly inhibits the protein expression of NFκB target genes ICAM-1 and MCP-1 while other targets like Bcl-xL and FLIP are not affected, thereby suggesting that the inhibition is promoter specific. This inhibition of ICAM-1 and MCP-1 by Nutlin-3 is again dependent on the p53 status in cells. Furthermore, we show that Nutlin-3 strongly inhibits protein expression of ICAM-1 and MCP-1 induced by IL1, another NFκB activating stimuli. Nutlin-3 does not inhibit Akt phosphorylation, IκBa phosphorylation, IκBa degradation, p65 modification or p65 DNA binding in the cell lines tested. This study suggests the potential of Nutlin-3 as a bitargeted anti-cancer drug by simultaneously causing p53 activation and NFκB suppression. It also suggests that Nutlin-3 could be evaluated for treatment of lung cancer as a single agent or in combination therapy by targeting its effect on ICAM-1 and MCP-1 which are known to be critical for cancer cell invasion, thereby downregulating tumor formation and metastasis. This study also suggests biomarkers of response for evaluation of Nutlin-3 in the clinic.

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Section: Nutlin-3 Downregulates Nfκb Pathwaymentioning

confidence: 92%

Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Dey

Wong²,

Bist³

et al. 2007

Cell Cycle

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“…PCAF is a histone acetyltransferase involved in the reversible acetylation of various transcriptional regulators, including the tumor suppressor protein p53 (23). Recently, Linares and colleagues have shown that PCAF possesses an intrinsic ubiquitination activity that is critical for controlling Hdm2 expression levels, and thus p53 (24) that is rarely mutated (5-10% of cases) or deleted at diagnosis in MM (25)(26). To examine whether these miRNAs could regulate PCAF, first we analyzed PCAF expression by q-RT-PCR (Fig.…”

Section: Several Mirnas Up-regulated In MM Target P300-cbp-associatedmentioning

confidence: 99%

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Pichiorri¹,

Suh²,

Ladetto

et al. 2008

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

511

555

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Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n ‫؍‬ 49) and CD138؉ bone marrow PCs from subjects with MM (n ‫؍‬ 16), monoclonal gammopathy of undetermined significance (MGUS) (n ‫؍‬ 6), and normal donors (n ‫؍‬ 6). We identified overexpression of miR-21, miR-106bϳ25 cluster, miR181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17ϳ92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17ϳ92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor , a gene involved in p53 regulation, as a bona fide target of the miR106bϳ25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.PCAF ͉ SOCS-1 ͉ tumor suppressor gene ͉ MGUS ͉ plasma cells

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“…Therefore, senescence is identified as an additional tumor suppressive mechanism in benign or premalignant cancer lesions [51]. Senescent cells remain metabolically active but acquire distinct changes in morphology and physiology characterized by enlarged cell size, chromatin condensation, changes in gene expression, and high levels of senescence-associated β-galactosidase.…”

Section: Role Of P53 In Cancer and Therapeuticsmentioning

confidence: 99%

Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53

Martinez-Rivera

Siddik

2012

Biochemical Pharmacology

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Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ~50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 “gain-of-resistance” phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild-type p53 cancers.

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Selective Pharmacologic Activation of the p53-Dependent Pathway as a Therapeutic Strategy for Hematologic Malignancies

Cited by 16 publications

References 24 publications

Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53

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