Abstract 5741: 6-((1,4-naphthoquinone-2-yl)methyl)thio-glucose conjugates, a novel targeted approach for advanced prostate cancer

Abstract The Warburg effect is a shift from oxidative phosphorylation to anaerobic glycolysis, accompanied by an enormous increase in glucose uptake into cancer cells. We have utilized this effect to design a new group of targeted 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker, which were cytotoxic to prostate cancer cells. Compound PeS-9 revealed the highest efficacy and selectivity, which was conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, it increased reactive oxygen species production and induced DNA double-strand breaks. Combinational therapy with PARP-inhibitor olaparib resulted in synergistic effects in homologous recombination-deficient cells. The underlying mode of PeS-9 cytotoxic action involved mitochondria targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspases-3 and -9, PARP cleavage, and apoptotic cell death. This process was stipulated by down-regulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by kinases p38, JNK1/2, and ERK1/2 was identified as an important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patients-derived tumoroids as well as in vivo resulting in decreased tumor growth and dissemination of prostate cancer cells to the lungs. No serious side effects were observed in animal models. This unique combination of anticancer properties makes PeS-9 an attractive candidate for targeted monotherapy against GLUT-1-overexpressing tumors and as a potential combination partner, especially with PARP inhibitors. Citation Format: Sergey Dyshlovoy, Tobias Busenbender, Dmitry Pelageev, Jessica Hauschild, Moritz Kaune, Lukas Böckelmann, Christoph Krisp, Mohamed Elsesy, Alexandra Zielinski, Thomas Mair, Simone Venz, Malte Kriegs, Konstantin Hoffer, Yuri Sabutski, Ksenia Borisova, Nadja Strewinsky, Svetlana Kovach, Ekaterina Khmelevskaya, Klaus Pantel, Hartmut Schlüter, Victor Anufriev, Derya Tilki, Markus Graefen, Wael Mansour, Carsten Bokemeyer, Gunhild von Amsberg. 6-((1,4-naphthoquinone-2-yl)methyl)thio-glucose conjugates, a novel targeted approach for advanced prostate cancer [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 5741.