PSMA-617 inhibits proliferation and potentiates the 177Lu-PSMA-617-induced death of human prostate cancer cells.

The human prostate–specific membrane antigen (PSMA) is substantially up-regulated in metastatic prostate cancer (PCa) cells. PSMA can be targeted by ¹⁷⁷Lu conjugated to PSMA-617, a high-affinity ligand for the PSMA. The binding of the radioligand, ¹⁷⁷Lu-PSMA-617, results in its internalisation and delivery of β-radiation into the cancer cells. However, PSMA-617, a component of the final product in the synthesis of the radioligand, may also play a role in the pathophysiology of PCa cells. The present study aimed to clarify the effects of PSMA-617 (10, 50 and 100 nM) on the expression of PSMA in PSMA-positive LNCaP cells, their proliferation, ¹⁷⁷Lu-PSMA-617-induced cell death by WST-1 and lactate dehydrogenase assays, immunohistochemistry, western blotting, immunofluorescence staining and uptake of ¹⁷⁷Lu-PSMA-617. PSMA-617 at 100 nM concentration induced cell-growth arrest, down-regulated cyclin D1 and cyclin E1 (by 43 and 36%, respectively) and up-regulated the cyclin-dependent kinase inhibitor p21^Waf1/Cip1 (by 48%). Immunofluorescence staining demonstrated reduced content of DNA, pointing to a lower rate of cell division. PSMA-617 (up to 100 nM) did not alter the uptake of ¹⁷⁷Lu-PSMA-617 into the LNCaP cells. Interestingly, simultaneous treatment with ¹⁷⁷Lu-PSMA-617 and PSMA-617 for 24 and 48 h substantially potentiated the cell-death promoting effects of the radioligand. In conclusion, the combination of impeding tumour cell proliferation by PSMA-617 and its potentiation of the radiation-induced cell death brought about by ¹⁷⁷Lu-PSMA-617 in PCa cells may considerably improve the outcome of the radiation therapy with ¹⁷⁷Lu-PSMA-617, especially in patients with decreased radiosensitivity of PCa cells to the radioligand. [ABSTRACT FROM AUTHOR]