MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death

Barbieri, Eveline; Mehta, Parth; Chen, Zaowen; Zhang, Linna; Slack, Andrew; Berg, Stacey L.; Shohet, Jason M.

doi:10.1158/1535-7163.mct-06-0305

Cited by 127 publications

(125 citation statements)

References 45 publications

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“…This favors a reduction of the dose of the chemotherapeutic agent to prevent the side effects without losing its effect as anti-cancer drug. Earlier studies have shown that Nutlin-3 is a potent sensitizer for standard radio-and chemotherapy (Barbieri et al, 2006;Cao et al, 2006;Coll-Mulet et al, 2006;Patton et al, 2006). Therefore, Nutlin-3 was combined with doxorubicin, which resulted in increased cell death, even with concentrations of doxorubicin that by itself had very little effect on cell survival.…”

Section: Regulation Of Drug Response By Mdm4mentioning

confidence: 99%

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Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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Section: Regulation Of Drug Response By Mdm4mentioning

confidence: 99%

“…Owing to these characteristics, Nutlin-3 has been tested for its synergistic effects with existing therapies. It has been shown that treatment with Nutlin-3 is synergistic with genotoxic drugs and radiation in cancer therapy (Barbieri et al, 2006;Cao et al, 2006;CollMulet et al, 2006;Patton et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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“…While this work was ongoing, several new studies confirm the synergism of Nutlin in chemotherapeutic control of NB cells in culture. 38,39 In sum, our findings identify p53 hyperubiquitylation as a mechanism that contributes to cytoplasmic sequestration and attenuation of p53 function in NB. This p53 hyperubiquitylation is due to an impaired p53-HAUSP interaction but can be reversed by inhibiting the p53-Hdm2 interaction.…”

Section: Discussionmentioning

confidence: 66%

Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma

et al. 2007

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Neuroblastoma (NB) is the most common solid malignancy in childhood and its prognosis is still generally poor. In contrast to many other cancers, mutations of the p53 tumor suppressor are rare. Instead, significant cytosolic sequestration of wtp53 is one of several mechanisms that attenuate p53 function in this cancer. Here, we report that aberrant p53 hyperubiquitylation contributes to p53 cytoplasmic sequestration in NB. NB lines constitutively harbor an elevated portion of wtp53 as stable ubiquitylated species confined to the cytoplasm. p53 hyperubiquitylation is not due to dysregulation by Hdm2 or proteasomal dysfunction. Instead, the defect lies in p53 regulation by HAUSP, a major p53-deubiquitylating enzyme. In contrast to non-NB cancer cells with nuclear p53 and normal ubiquitylation, p53 from NB cells shows impaired HAUSP interaction. Conversely, interference with p53 hyperubiquitylation in NB cells by Nutlin 3a or by a C-terminal p53 peptide (aa 305-393) results in p53 relocalization from the cytoplasm to the nucleus, and in case of Nutlin, in reactivation of p53's transcriptional and apoptotic functions. Moreover, nutlin and camptothecin act synergistically in inducing NB cell apoptosis. Hence, this study strengthens the rationale for targeting p53 deubiquitylation by drugs like Nutlin as a promising new strategy in NB therapy. Neuroblastoma (NB) is the most common solid malignancy in childhood and still accounts for more pediatric cancer deaths than any other cancer type. 1 The p53 tumor suppressor induces cell growth arrest, apoptosis and senescence in response to various types of stress and is mutated in over 50% of cancers. 2 However, in NB p53 mutations are exceedingly rare and occur in o2%, typically in relapsed tumors after therapy. 3,4 Instead, subcellular mislocalization of wtp53 with constitutive cytoplasmic sequestration represents one of several alternative mechanisms to inactivate p53 function in this cancer. Moll et al. 5 originally found cytoplasmic accumulation of p53 in 96% of primary undifferentiated NB tumors, whereas differentiated tumors (ganglioneuromas) lacked detectable levels of p53. Although some NB lines show predominantly nuclear p53 staining, 6 many NB cell lines also exhibit abnormal cytoplasmic p53 localization. [7][8][9][10][11][12][13] Cytoplasmic sequestration of wtp53 correlates with attenuation of DNA damage-induced G1 arrest 6,7 and apoptosis 13,14 in NB cell lines, since this interferes with p53's function as a transcription factor in the nucleus. Furthermore, Wolff et al. 15 reported that wtp53 in NB is in a conformation that is refractory to integration into transcriptional complexes, adding to transcriptional inactivity.In growing, unstressed cells p53 levels are very low owing to rapid degradation via the ubiquitin-proteasome pathway. Hdm2, the major E3 ligase which itself is a target gene of p53, ubiquitylates p53, thus constituting a negative-feedback loop. 16,17 Importantly, this ubiquitylation of p53 is required for its nuclear export via the export recepto...

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“…If the feedback loop is interrupted by an agent such as Nutlin-3a, the tumor cell will undergo apoptosis. Nutlin-3a has been studied as an effective agent to induce cell cycle arrest and apoptosis in some tumors, and has been found to increase radiosensitivity of H460 and Val138 cells [16], and to sensitize cells to chemotherapeutic agents such as cisplatin and etoposide [17]. To date, there has been no study of Nutlin-3a as a chemosensitizer for the commonly used agent paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

“…Nutlins can release p53 from the negative control of MDM2 and activate the p53 pathway to promote cell cycle arrest and apop-tosis in cancer cells that express wild-type p53. Nutlin-3a increases radiosensitivity of H460 and Val138 cells [16], and sensitizes cancer cells to chemotherapeutic agents such as cisplatin, and etoposide [17]. However, some researchers found that Nutlins can protect non-malignant cells and tissues [18,19].…”

mentioning

confidence: 99%

MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel

et al. 2012

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The p53 pathway has an important role in cell cycle arrest and apoptosis. Downregulated levels of p53 have been shown to increase resistance to the cytotoxic effects of chemotherapy or radiotherapy. MDM2 (murine double minute 2) is able to bind p53 and modulate its transcriptional activity and stability. We studied the effect of Nutlin-3a, an MDM2 antagonist, on the response of non-small cell lung cancer cell lines, A549 (p53+/+) and H1299 (p53/), to paclitaxel (Taxol). A549 cells treated with Nutlin-3a plus paclitaxel showed a significant increase in MDM2 and wild-type p53 protein, a marked increase in the number of cells in the G0-G1 and G2-M phases, and a significant decrease in the percentage of cells in the S phase. The percentage of apoptotic A549 cells treated with 10 mol/L Nutlin-3a plus 10 nmol/L paclitaxel was significantly lower than those treated with paclitaxel alone, and was also lower than that observed in H1299 cells. MTT assays demonstrated that Nutlin-3a plus paclitaxel also significantly reduced the sensitivity of A549 cells to paclitaxel compared with that of H1299 cells. In conclusion, Nutlin-3a mediates the cytotoxic effect of paclitaxel depending on p53 status. It may also protect wild-type p53 cells from mitotic chemotherapeutics.non-small cell lung carcinoma, p53, MDM2 antagonist, paclitaxel Citation:Shen H C, Dong W, Gao D W, et al. MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel.

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MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death

Cited by 127 publications

References 45 publications

Role of Mdm4 in drug sensitivity of breast cancer cells

Role of Mdm4 in drug sensitivity of breast cancer cells

Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma

MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel

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