Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype

Abstract

A majority of mesothelioma had the wild-type p53 genotype but was defective of p53 functions primarily due to a genetic defect in INK4A/ARF region. We examined a growth suppressive activity of CP-31398 which was developed to restore the p53 functions irrespective of the genotype in mesothelioma with wild-type or mutated p53. CP-31398 up-regulated p53 levels in cells with wild-type p53 genotype but induced cell growth suppression in a p53-independent manner. In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. We investigated a combinatory effect of CP-31398 and nutlin-2a and found the combination produced synergistic growth inhibition in mesothelioma with the wild-type p53 but not with mutated p53. Western blot analysis showed that the combination increased p53 and the phosphorylation levels greater than treatments with the single agent, augmented cleavages of PARP and caspase-3, and decreased phosphorylated FAK levels. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.

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Abbreviations

FAK:

Focal adhesion kinase

IC50:

Half maximal inhibitory concentration

CI:

Combination index

Fa:

Fractions affected

NF2:

Neurofibromatosis type 2

AMPK:

AMP-activated protein kinase

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (KAKENHI: 16K09598, 17K10617, 18K15937) and Grant-in-aid from the Nichias Corporation. These funding bodies have not participated in the design of the study, collection, analysis, interpretation of data, or writing of the manuscript.

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Correspondence to Dr. Masatoshi Tagawa.

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The authors declare that there is no conflict of interests in this research. We obtained a grant from Nichias Corporation. It is not a pharmaceutical company but a company making industrial products for building, automobiles and pipes (see http://www.nichias.co.jp/). The grant is as a kind of their mécénat activities, corporate social contributions, which is aimed to assist for medical research for intractable cancer treatments. We are thereby irrelevant to any employment, consultancy, patents or products in development or marketed products to the company. All the authors agree to publish the data included in the manuscript.

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Zhong, B., Shingyoji, M., Hanazono, M. et al. Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype. Apoptosis (2020). https://doi.org/10.1007/s10495-020-01612-6

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Keywords

  • Mesothelioma
  • CP-31398
  • Nutlin-3a
  • p53
  • FAK