Details

Autor(en) / Beteiligte

• Moon, David
• Hauck, J. Spencer
• Jiang, Xue
• Quang, Holly
• Xu, Lingfan
• Zhang, Fan
• Gao, Xia
• Wild, Robert
• Everitt, Jeffrey I.
• Macias, Everardo
• He, Yiping
• Huang, Jiaoti

Titel

Targeting glutamine dependence with DRP‐104 inhibits proliferation and tumor growth of castration‐resistant prostate cancer

Ist Teil von

• The Prostate, 2024-03, Vol.84 (4), p.349-357

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Background Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration‐resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6‐diazo‐5‐oxo‐l‐norleucine (DON) blocks both carbon and nitrogen pathways but has dose‐limiting toxicity. The prodrug DRP‐104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP‐104 remains unclear. Methods Human PCa cell lines (LNCaP, LAPC4, C4‐2/MDVR, PC‐3, 22RV1, NCI‐H660) were treated with DRP‐104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP‐104 on glutamine pathways. Efficacy of DRP‐104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI‐H660. Results DRP‐104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP‐104 treated CRPC cells were rescued by the addition of nucleosides. DRP‐104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. Conclusions The prodrug DRP‐104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP‐104 represents a promising therapeutic strategy for CRPC.