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.

• Authors: Boya Zhong, Masato Shingyoji, Michiko Hanazono, Thi Thanh Nguyễn, Takao Morinaga, Yuji Tada, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 25 Issue 7-8 Pg. 535-547 (08 2020) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 32468177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Piperazines
• Pyrimidines
• Tumor Suppressor Protein p53
• nutlin 3
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Checkpoint Kinase 2
• Focal Adhesion Kinase 1
• PTK2 protein, human
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• CP 31398

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1 (genetics, metabolism)
• Checkpoint Kinase 2 (genetics, metabolism)
• Drug Synergism
• Epithelium (drug effects, metabolism, pathology)
• Focal Adhesion Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Genotype
• Humans
• Imidazoles (pharmacology)
• Phosphorylation (drug effects)
• Piperazines (pharmacology)
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Signal Transduction
• Tumor Suppressor Protein p53 (agonists, genetics, metabolism)
• Ubiquitination (drug effects)