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The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer

(2015) ONCOTARGET. 6(26). p.22666-22679
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Abstract
The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3.
Keywords
synergism, SMALL-MOLECULE ANTAGONISTS, NSCLC, p53, MDM2, cisplatin, MDM2 ANTAGONISTS, MUTANT P53, IN-VITRO, PATHWAY, CHEMOTHERAPY, ACTIVATION, THERAPY, TP53, INHIBITORS

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Chicago
Deben, Christophe, An Wouters, Ken Op de Beeck, Jolien van den Bossche, Julie Jacobs, Karen Zwaenepoel, Marc Peeters, et al. 2015. “The MDM2-inhibitor Nutlin-3 Synergizes with Cisplatin to Induce P53 Dependent Tumor Cell Apoptosis in Non-small Cell Lung Cancer.” Oncotarget 6 (26): 22666–22679.
APA
Deben, C., Wouters, A., Op de Beeck, K., van den Bossche, J., Jacobs, J., Zwaenepoel, K., Peeters, M., et al. (2015). The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer. ONCOTARGET, 6(26), 22666–22679.
Vancouver
1.
Deben C, Wouters A, Op de Beeck K, van den Bossche J, Jacobs J, Zwaenepoel K, et al. The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer. ONCOTARGET. 2015;6(26):22666–79.
MLA
Deben, Christophe, An Wouters, Ken Op de Beeck, et al. “The MDM2-inhibitor Nutlin-3 Synergizes with Cisplatin to Induce P53 Dependent Tumor Cell Apoptosis in Non-small Cell Lung Cancer.” ONCOTARGET 6.26 (2015): 22666–22679. Print.
@article{7024122,
  abstract     = {The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3.},
  author       = {Deben, Christophe and Wouters, An and Op de Beeck, Ken and van den Bossche, Jolien and Jacobs, Julie and Zwaenepoel, Karen and Peeters, Marc and Van Meerbeeck, Jan and Lardon, Filip and Rolfo, Christian and Deschoolmeester, Vanessa and Pauwels, Patrick},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {synergism,SMALL-MOLECULE ANTAGONISTS,NSCLC,p53,MDM2,cisplatin,MDM2 ANTAGONISTS,MUTANT P53,IN-VITRO,PATHWAY,CHEMOTHERAPY,ACTIVATION,THERAPY,TP53,INHIBITORS},
  language     = {eng},
  number       = {26},
  pages        = {22666--22679},
  title        = {The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer},
  url          = {http://dx.doi.org/10.18632/oncotarget.4433},
  volume       = {6},
  year         = {2015},
}

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