@article{liukaityteCombinationPSMATargeting2025,
	title = {Combination of {PSMA} targeting alpha-emitting radioligand [212Pb]Pb-{AB}001 with {BET} bromodomain inhibitors in in vitro prostate cancer models},
	volume = {42},
	issn = {1559-131X},
	url = {https://doi.org/10.1007/s12032-025-02925-9},
	doi = {10.1007/s12032-025-02925-9},
	abstract = {The alpha-emitting radioligand [212Pb]Pb-{AB}001, targeting prostate-specific membrane antigen ({PSMA}), is a promising therapy approach for prostate cancer. Bromodomain and extra-terminal ({BET}) protein inhibitors, such as {AZD}5153 and {JQ}1, disrupt oncogenic transcriptional programs by altering chromatin structure. This study evaluated whether {BET} inhibition enhances the efficacy of radioligand therapy. Cytotoxic effects of [212Pb]Pb-{AB}001 alone and in combination with {BET} inhibitors were assessed in 2D monolayers and a 3D spheroid model of {PSMA}-positive C4-2 prostate cancer cells. Cell viability, cell cycle alterations, and {DNA} damage were assessed using viability assays and flow cytometry. Spheroid growth and viability were assessed by fluorescence microscopy. {AZD}5153 was more potent than {JQ}1 in reducing cell proliferation. [212Pb]Pb-{AB}001 induced activity- and time-dependent cytotoxicity with a delayed apoptotic response. {BET} inhibitors induced G1 arrest, while [212Pb]Pb-{AB}001 caused G2 arrest. Combination treatment reduced cell viability in an additive manner but did not further affect cell cycle distribution or increase apoptosis compared with [212Pb]Pb-{AB}001 alone. γH2AX staining in 2D models showed an activity- and time-dependent increase in {DNA} damage at 1, 3 and 6 days post-treatment with [212Pb]Pb-{AB}001. {BET} inhibitors alone induced minimal γH2AX, and combination treatments did not enhance {DNA} damage beyond [212Pb]Pb-{AB}001 alone. In 3D spheroids, combination treatment led to synergistic growth suppression. In conclusion, these findings indicate that therapeutic inhibition of {BET} bromodomain in combination with the alpha-emitting radioligand [212Pb]Pb-{AB}001 could significantly enhance tumour control and should be further evaluated in metastatic prostate cancer models.},
	pages = {362},
	number = {8},
	journaltitle = {Medical Oncology},
	shortjournal = {Med Oncol},
	author = {Liukaityte, Rugile and Stenberg, Vilde Yuli and Kleinauskas, Andrius and Juzenas, Petras and Urbanucci, Alfonso and Juzeniene, Asta},
	urldate = {2026-01-30},
	date = {2025-07-22},
	langid = {english},
	keywords = {Bromodomain and extra-terminal proteins, Cell cycle, Combination treatment, Targeted alpha therapy, Targeted radionuclide therapy, scientific-publication},
}