Abstract 6933: Ru(II)-thymine complex inhibits NF-κB activation, suppressing acute myeloid leukemia stem cells

Abstract Acute myeloid leukemia (AML) is a deadly blood cancer caused by leukemia blasts that fail to develop properly. AML has a significant relapse rate, which is attributed to a subset of cells known as leukemia stem cells (LSCs). Herein, we evaluated the ability of a Ru(II)-thymine complex (RTC) with the formula [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thymine, and bipy = 2, 2'-bipyridine) to suppress AML LSCs. RTC exhibited strong cytotoxicity against solid and hematologic malignancies and inhibited primary AML LSCs, as evidenced by a decrease in the CD34+CD38- cell population. RTC decreased the number of CD34+ and CD123+ cells in the AML cell line KG-1a, which has a similar population to LSC. RTC-treated NSG mice bearing KG-1a xenografts had a reduced number of leukemic blasts in the bone marrow. RTC-treated KG-1a cells showed increased DNA fragmentation, active caspase-3 and cleaved PARP (Asp 214) levels, and mitochondrial superoxide. The pancaspase inhibitor Z-VAD-(OMe)-FMK, but not the antioxidant N-acetylcysteine, partially reduced RTC-induced cell death in KG-1a cells, demonstrating that RTC causes caspase-mediated apoptosis via an oxidative stress-independent pathway. In molecular mechanism investigations, transcripts of the NF-κB inhibitor NFKBIA were increased, and the level of NF-κB p65 phosphorylated at Ser529 residue was reduced in RTC-treated KG-1a cells. This suggests that RTC may block NF-κB signaling. Altogether, these data suggest the anti-AML potential of RTC in AML LSCs via suppression of NF-κB signaling. Citation Format: Maiara de S. Oliveira, Ingrid R. Dias, Rafaela G. Costa, Ana Carolina B. Rodrigues, Suellen L. Silva, Milena B. Soares, Rosane B. Dias, Ludmila F. Valverde, Clarissa A. Rocha, Alzir A. Batista, Rodrigo S. Correa, Valdenizia R. Silva, Eugênia T. Pina, Daniel P. Bezerra. Ru(II)-thymine complex inhibits NF-κB activation, suppressing acute myeloid leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6933.