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
Autor: | Masato Shingyoji, Thi Thanh Nguyễn, Masatoshi Tagawa, Hideaki Shimada, Takao Morinaga, Michiko Hanazono, Kenzo Hiroshima, Yuji Tada, Boya Zhong |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Genotype Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Ataxia Telangiectasia Mutated Proteins Epithelium Piperazines Dephosphorylation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Western blot Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Phosphorylation Cell Proliferation Pharmacology biology medicine.diagnostic_test Cell growth Cell Cycle Biochemistry (medical) Imidazoles Ubiquitination Wild type Drug Synergism Proto-Oncogene Proteins c-mdm2 Cell Biology Gene Expression Regulation Neoplastic Checkpoint Kinase 2 Pyrimidines 030104 developmental biology chemistry Focal Adhesion Kinase 1 030220 oncology & carcinogenesis Checkpoint Kinase 1 Cancer research biology.protein Mdm2 Tumor Suppressor Protein p53 Growth inhibition Protein Processing Post-Translational Signal Transduction |
Zdroj: | Apoptosis. 25:535-547 |
ISSN: | 1573-675X 1360-8185 |
Popis: | 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. |
Databáze: | OpenAIRE |
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