Flörkemeier Inken, Hotze Hannah L, Heyne Anna Lena, Hildebrandt Jonas, Weimer Jörg P, Hedemann Nina, Rogmans Christoph, Holthaus David, Siebert Frank-André, Hirt Markus, Polten Robert, Morgan Michael, Klapdor Rüdiger, Schambach Axel, Dempfle Astrid, Maass Nicolai, van Mackelenbergh Marion T, Clement Bernd, Bauerschlag Dirk O
Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrecht University of Kiel, 24118 Kiel, Germany.
Int J Mol Sci. 2025 Mar 21;26(7):2829. doi: 10.3390/ijms26072829.
Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed. The newly developed dual topoisomerase inhibitor P8-D6, with its outstanding ability to induce apoptosis, could be a promising option. In this study, the efficacy of P8-D6 in combination with radiochemotherapy against cervical carcinoma was investigated in established cell lines and in a translational approach in ex vivo patient cells by measuring the cytotoxicity, cell viability and caspase activity in vitro in 2D and 3D cell cultures. Treatment with P8-D6 resulted in significantly greater cytotoxicity and apoptosis induction compared to standard therapeutic cisplatin in both 2D and 3D cell cultures. Specifically, a considerably stronger anti-proliferative effect was observed. The treatment also led to morphological changes and a loss of membrane integrity in the 3D spheroids. Radiotherapy also benefited greatly from P8-D6 treatment. In fact, P8-D6 was a more potent radiosensitizer than cisplatin. Simple synthesis, favorable physicochemical properties and high potency make P8-D6 a promising cervical cancer drug candidate.
尽管在疫苗接种和早期检测方面取得了进展，但近几十年来宫颈癌的病例总数和死亡人数仍在稳步上升，使其成为全球女性中第四大常见癌症类型。特别是低收入国家在宫颈癌资源有限和治疗受限方面面临困难。因此，需要易于生产的有效药物。新开发的双拓扑异构酶抑制剂P8-D6具有出色的诱导细胞凋亡能力，可能是一个有前景的选择。在本研究中，通过在2D和3D细胞培养中测量体外细胞毒性、细胞活力和半胱天冬酶活性，在已建立的细胞系以及采用离体患者细胞的转化方法中研究了P8-D6联合放化疗对宫颈癌的疗效。与标准治疗药物顺铂相比，在2D和3D细胞培养中，P8-D6处理均导致显著更高的细胞毒性和凋亡诱导。具体而言，观察到了明显更强的抗增殖作用。该处理还导致3D球体出现形态变化和膜完整性丧失。放疗也从P8-D6处理中受益匪浅。事实上，P8-D6是一种比顺铂更有效的放射增敏剂。简单的合成、良好的理化性质和高效性使P8-D6成为一种有前景的宫颈癌候选药物。
