Dataset associated with ''Cytotoxicity and cell cycle changes in prostate cancer cells with differing PSMA expression and p53 status after treatment with PSMA-targeting radioligand [212Pb]Pb-AB001''

ABSTRACT Targeted alpha therapy holds promise for treating advanced prostate cancer, but the interplay between prostate-specific membrane antigen (PSMA) expression, p53 status, and downstream cell fate remains poorly defined. This study evaluates the cytotoxic and cell cycle effects of the alpha-emitting radioligand [212Pb]Pb-AB001 in prostate cancer cell lines with differing PSMA expression and p53 status: C4-2 (PSMA+/TP53-wild-type) and PC-3 PIP (PSMA+++/ TP53-null). [212Pb]Pb-AB001 significantly inhibited proliferation and clonogenic survival in both cell lines in an activity-dependent manner. At 95% clonogenic inhibition, both cell lines exhibited G2-phase arrest, S-phase suppression and reduced mitotic entry on day 1. At higher activities, PC-3 PIP cells showed polyploidy, and features consistent with mitotic catastrophe and senescence. Cytotoxicity was more pronounced in C4-2 3D spheroid models than in 2D monolayers, suggesting contribution of crossfire and bystander effects. Total cell-bound activity, rather than added activity, better predicted radiotoxicity in both TP53-wild-type and TP53-null cell lines, indicating that its therapeutic effect is primarily governed by PSMA-mediated uptake rather than p53 status. These results support the therapeutic potential of [212Pb]Pb-AB001 across cells with varying TP53 status and suggest that combining [212Pb]Pb-AB001 with DNA repair or checkpoint inhibitors may enhance treatment efficacy.摘要 靶向α治疗在晚期前列腺癌的治疗中具有应用前景，但前列腺特异性膜抗原（prostate-specific membrane antigen, PSMA）表达、p53状态与下游细胞命运之间的相互作用，目前仍未得到充分阐明。本研究针对PSMA表达水平与p53状态各异的前列腺癌细胞系，评估了α发射型放射性配体[212Pb]Pb-AB001的细胞毒性与细胞周期效应，所选用的细胞系为C4-2（PSMA+/TP53野生型）与PC-3 PIP（PSMA+++/TP53缺失型）。[212Pb]Pb-AB001以活性依赖的方式显著抑制了两种细胞系的增殖与克隆形成存活率。当克隆形成抑制率达到95%时，两种细胞系在第1天均出现G2期阻滞、S期抑制以及有丝分裂进入减少的现象。当活性升高时，PC-3 PIP细胞出现多倍体现象，以及与有丝分裂灾难和细胞衰老相符的特征。C4-2的3D球体模型中的细胞毒性较2D单层细胞更为显著，这提示交叉火力效应与旁观者效应参与了其作用过程。在TP53野生型与TP53缺失型细胞系中，细胞结合总放射性活性而非添加的放射性活性，能更好地预测放射毒性，这表明其治疗效应主要由PSMA介导的摄取所决定，而非p53状态。上述结果证实了[212Pb]Pb-AB001在TP53状态各异的细胞中的治疗潜力，并提示将[212Pb]Pb-AB001与DNA修复抑制剂或检查点抑制剂联合使用，或可提升治疗效果。