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
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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