Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma

Stühmer, Thorsten; Chatterjee, Manik; Hildebrandt, Martin; Herrmann, Pia; Gollasch, Hella; Gerecke, Christian; Theurich, Sebastian; Cigliano, Luisa; Manz, Rudolf A.; Daniel, Peter T.; Bommert, Kurt; Vassilev, Lyubomir T.; Bargou, Ralf C.

doi:10.1182/blood-2005-04-1489

Cited by 160 publications

(177 citation statements)

References 29 publications

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“…The proportion of Annexin V positive cells was also markedly increased by Nultin-3 in those cells showing a high Caspase-3/7 activity, but not in other cells (Supplementary Figure 1A). In agreement with previous reports that leukemia cells are sensitive to p53-induced apoptosis (Kojima et al, 2005;Stuhmer et al, 2005;Secchiero et al, 2006), all leukemia cell lines that we tested underwent apoptosis ( Figure 1a). Next, we investigated whether the apoptotic response induced by Nutlin-3 correlated with its antitumor response.…”

Section: Resultssupporting

confidence: 80%

“…Nutlin-3, a selective small-molecule inhibitor of the p53-Mdm2 interaction, activates the p53 pathway in vitro and in vivo, leading to cell-cycle arrest and/or apoptosis in various cancer cells with wild-type p53 including neuroblastoma (Van Maerken et al, 2006), retinoblastoma (Laurie et al, 2006), osteosarcoma (Vassilev et al, 2004) and leukemia (Stuhmer et al, 2005;Coll-Mulet et al, 2006). In contrast, the response of normal cells, such as wild-type fibroblasts, to Nutlin-3 is largely limited to a reversible growth arrest (Vassilev et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

et al. 2008

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

et al. 2008

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“…In some cases, growth arrest at the G1 and G2 phases of the cell cycle by Nutlin-3a can protect proliferating cells from the cytotoxic effect of mitotic poisons (Carvajal et al, 2005). Previous findings have suggested that Nutlins may offer a new therapeutic option to patients with tumors that express wild-type p53 either as single agent (Vassilev, 2005;Tovar et al, 2005) or as combination therapy (Kojima et al, 2005;Stuhmer et al, 2005). In contrast, tumor cells with mutant p53 are resistant to Nutlin-3a (Carvajal et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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“…Among the various WT p53 activators, nutlins have probably been the most studied in human cancers. While most of the efforts have focused on using nutlin-3 as a single agent for applications in oncology, some recent studies have also combined nutlin-3 with chemotherapeutic agents and seen potentiation of activity of these chemotherapeutics in vitro, in acute myelogenous leukaemia (Kojima et al, 2005), multiple myeloma (Stuhmer et al, 2005) and chronic lymphocytic leukaemia (Coll-Mulet et al, 2006). These initial studies definitely look promising and warrant more detailed studies in animal models.…”

Section: Drug Synergy and Biomarkers Of Responsementioning

confidence: 99%

Updates on p53: modulation of p53 degradation as a therapeutic approach

2008

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Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma

Cited by 160 publications

References 29 publications

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Updates on p53: modulation of p53 degradation as a therapeutic approach

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