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

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.