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Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma

(2017) ONCOTARGET. 8(34). p.57047-57057
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Abstract
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.
Keywords
neuroblastoma, idasanutlin, p53, venetoclax, synergism, P53 PATHWAY, SENSITIZES NEUROBLASTOMA, ANTAGONIST NUTLIN-3, ANTITUMOR-ACTIVITY, CHEMOTHERAPY, RESISTANCE, COMBINATION, MECHANISM, LEUKEMIA, GROWTH

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Citation

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Chicago
Van Goethem, Alan, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Franki Speleman, Jason Shohet, Jo Vandesompele, and Tom Van Maerken. 2017. “Dual Targeting of MDM2 and BCL2 as a Therapeutic Strategy in Neuroblastoma.” Oncotarget 8 (34): 57047–57057.
APA
Van Goethem, A., Yigit, N., Moreno-Smith, M., Vasudevan, S. A., Barbieri, E., Speleman, F., Shohet, J., et al. (2017). Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. ONCOTARGET, 8(34), 57047–57057.
Vancouver
1.
Van Goethem A, Yigit N, Moreno-Smith M, Vasudevan SA, Barbieri E, Speleman F, et al. Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. ONCOTARGET. 2017;8(34):57047–57.
MLA
Van Goethem, Alan, Nurten Yigit, Myrthala Moreno-Smith, et al. “Dual Targeting of MDM2 and BCL2 as a Therapeutic Strategy in Neuroblastoma.” ONCOTARGET 8.34 (2017): 57047–57057. Print.
@article{8538409,
  abstract     = {Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.},
  author       = {Van Goethem, Alan and Yigit, Nurten and Moreno-Smith, Myrthala and Vasudevan, Sanjeev A and Barbieri, Eveline and Speleman, Franki and Shohet, Jason and Vandesompele, Jo and Van Maerken, Tom},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {neuroblastoma,idasanutlin,p53,venetoclax,synergism,P53 PATHWAY,SENSITIZES NEUROBLASTOMA,ANTAGONIST NUTLIN-3,ANTITUMOR-ACTIVITY,CHEMOTHERAPY,RESISTANCE,COMBINATION,MECHANISM,LEUKEMIA,GROWTH},
  language     = {eng},
  number       = {34},
  pages        = {57047--57057},
  title        = {Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma},
  url          = {http://dx.doi.org/10.18632/oncotarget.18982},
  volume       = {8},
  year         = {2017},
}

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