Targeting breast cancer with the new dual topoisomerase inhibitor P8-D6
Flörkemeier I.1,2, Steinhauer T.N.2, Clement B.2, Bauerschlag D.O.1
1UKSH Kiel, Department of Gynecology and Obstetrics, Kiel, Deutschland, 2Christian-Albrechts-University, Pharmaceutical Institute, Kiel, Deutschland
Introduction: Breast cancer constitutes the leading cause of cancer death among females1;2. Thus, the development of innovative cytotoxic compounds with suitable physicochemical properties has a high clinical need in cancer therapy. Although options have improved, breast cancer is still not sufficiently treatable due to chemotherapy resistance and treatment limitations by side effects. P8-D6 is a new effective inductor of apoptosis by acting as a dual topoisomerase inhibitor.
Its outstanding antitumoral property was shown in NCI-60-DTP-human-tumor-cell-line-screening (GI50/60value: 49nM) and in further in vitro testings3,4.
Methods: The potential of P8-D6 treatment to reduce proliferation and induce apoptosis in various established breast cancer cells and ex vivo primary cancer cells were determined by emission spectroscopy and microscopy. For better comparison, cells were treated with different concentrations of P8-D6 and standard therapeutics for 48h. Likewise, the effects on non-cancer cells were analysed and hepatotoxicity of P8-D6 was investigated. The expression levels of topoisomerase I/II were measured by western blot. Fluorescence microscopy showed whether P8-D6 reach its target.
Results: The results indicate a significantly increase of apoptosis in cancer cells by P8-D6 than its reference drugs. Non-cancer cells were slightly effected. No hepatotoxic effect in in vitro studies was seen. By staining, P8-D6 was detected in the nuclei.
Conclusion: P8-D6 has promising antitumor properties in in vitro studies on breast cancer. It has fewer side effects on normal cells than reference drugs and no hepatotoxic effect. Furthermore P8-D6 should be tested in 3D culture. P8-D6 is a strong and rapid inductor of apoptosis.