bims-p53act Biomed News
on p53 mutations and anti-cancer therapy response
Issue of 2026–02–22
two papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears
  1. Carbon-11 Isotopic Radiolabeling of CP31398 and Development of a Fluorine-18 Derivative to Target Protein p53 with PET Imaging.
  2. Synergistic RU486 and olaparib therapy enhances apoptosis in endometriosis by simultaneously targeting hormonal signalling and DNA repair.
  1. ACS Omega. 2026 Feb 10. 11(5): 7142-7150
    Carbon-11 Isotopic Radiolabeling of CP31398 and Development of a Fluorine-18 Derivative to Target Protein p53 with PET Imaging.
    Sébastien Beuché, Soizic Martin Aubert, Philippe Robin, Caroline Denis, Denis Servent, Bertrand Kuhnast, Charles Truillet, Fabien Caillé.
      Mutant protein p53, a central driver of pro-oncological deregulations, is widely recognized as a biomarker of cancer aggressiveness and therapy resistance. In a personalized medicine perspective, positron emission tomography (PET) imaging of mutant p53 would be a powerful tool for patient stratification and drug development. However, to date, no PET radiotracers directly targeting mutant p53 have been reported. Inspired by the CP31398 drug, which stabilizes p53 conformation and treats tumors expressing mutant p53, we designed two novel PET radiotracers labeled with either carbon-11 by isotopic labeling or fluorine-18, namely [11C]CP31398 and [18F]FG-CP31398. The nonradioactive fluorinated analogue was synthesized, as well as the two radiolabeling precursors. Optimization of the radiomethylation with carbon-11 of the phenol precursor was achieved, and automated radiosynthesis of [11C]CP31398 afforded the ready-to-inject radiotracer with 40 ± 13% radiochemical yield and 39 ± 12 GBq/μmol (n = 6) molar activity after quality control. Automated radiofluorination with 18F-fluoride by aliphatic SN2 of a tosylate precursor afforded the ready-to-inject [18F]FG-CP31398 in 10 ± 4% radiochemical yield (RCY) and 80 ± 39 GBq/μmol (n = 4) molar activity after quality control. Binding experiments performed with [18F]FG-CP31398 on HEK-293T cells transfected with a green fluorescent protein-p53 wild-type plasmid, with or without presaturation with CP31398, demonstrated that despite the chemical modification performed on this compound, [18F]FG-CP31398 was still able to bind specifically to the cell with ca. 20% nonspecific binding. However, autoradiography experiments performed after the incubation of either [11C]CP31398 or [18F]FG-CP31398 on H358 (p53 positive) and A549 (p53 negative) tumor slices derived from human lung cancer cells revealed that both tracers were not able to bind the p53-positive cells. Surprisingly, a specific fixation demonstrated by presaturation experiments was observed for both radiotracers on the p53-negative A549 cells. Overall, our findings indicate that neither CP31398 nor FG-CP31398 binds directly to p53 but instead interacts with an unidentified target. While unsuitable for p53 imaging, these radiotracers may serve as valuable tools to unravel the controversial mechanism of action of CP31398.
    DOI:  https://doi.org/10.1021/acsomega.5c06415
  2. Br J Pharmacol. 2026 Feb 18.
    Synergistic RU486 and olaparib therapy enhances apoptosis in endometriosis by simultaneously targeting hormonal signalling and DNA repair.
    Yujie Peng, Meng Zhang, Libo Zhu, Wenqiang Qian, Jingjing Yan, Huidi Jiang, Yu Xin, Ying Zhang, Dongli Sun, Weidong Fei, Mengdan Zhao.
       BACKGROUND AND PURPOSE: Endometriosis is a chronic, hormone-dependent disorder characterized by ectopic implantation of endometrial tissue, often accompanied by pain and infertility. Although the progesterone receptor modulator RU486 is effective for pain relief, its impact on lesion regression is limited, possibly due to apoptosis resistance and overexpression of PARP1 in endometriotic cells. This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53-dependent apoptosis in endometriotic lesions.
    EXPERIMENTAL APPROACH: Primary ectopic endometrial stromal cells (EESCs) were used to assess the effects of RU486 and olaparib on cytotoxicity, apoptosis, DNA damage, mitochondrial membrane potential, and cell migration. Mechanistic investigations included flow cytometry, western blotting, RT-qPCR, immunofluorescence, and comet assays. A murine endometriosis model was established to evaluate in vivo lesion suppression, pain behaviour, hormone levels, and treatment safety following combination therapy.
    KEY RESULTS: RU486 and olaparib exhibited strong synergy at a 1:4 ratio, significantly enhancing apoptosis in EESCs by coactivating p53 through distinct mechanisms-transcriptional up-regulation by RU486 and posttranslational stabilization by olaparib. This synergy intensified Bax/Bcl-2-mediated mitochondrial dysfunction, caspase-3 activation, and PARP1 cleavage. In vivo, the combination therapy achieved a 77.5% lesion weight regression, significantly exceeding monotherapies, while maintaining robust analgesic effects. Histological and molecular analyses confirmed DNA damage and enhanced apoptosis in lesions.
    CONCLUSION AND IMPLICATIONS: The combination medication enhanced apoptotic sensitivity in endometriosis by restoring p53 activity through targeting hormonal signalling and DNA repair pathways. This strategy offered strong potential for clinical translation.
    Keywords:  RU486; apoptosis; endometriosis; olaparib; p53
    DOI:  https://doi.org/10.1111/bph.70360
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