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.

多数间皮瘤具有野生型p53基因型，但主要由于INK4A / ARF区的遗传缺陷而导致p53功能缺陷。我们检查了CP-31398的生长抑制活性，该活性被开发用于恢复p53功能，而与间皮瘤中野生型或突变的p53的基因型无关。CP-31398上调具有野生型p53基因型的细胞中的p53水平，但以不依赖p53的方式诱导细胞生长抑制。相反，具有野生型p53的MDM2抑制剂nutlin-3a增加了间皮瘤中p53和p21的水平基因型和产生的生长抑制作用。我们研究了CP-31398和nutlin-2a的联合作用，发现该组合在间皮瘤中与野生型p53产生了协同的生长抑制作用，但对突变的p53却没有产生协同作用。蛋白质印迹分析表明，与单药治疗相比，该组合增加的p53和磷酸化水平更高，PARP和caspase-3的裂解增加，磷酸化FAK水平降低。CP-31398和FAK抑制剂defactinib的组合也达到了协同抑制作用，并且pAK的去磷酸化水平高于单次治疗，从而增加了p53。这些数据表明，与MDM2或FAK抑制剂联用的p53激活CP-31398具有生长抑制作用，并提示p53升高与FAK失活之间可能存在相互关系。