Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity

Functional Analyses of RUNX3 and CaMKIINα in Ovarian Cancer Cell Lines Reveal Tumor-Suppressive Functions for CaMKIINα and Dichotomous Roles for RUNX3 Transcript Variants

(1) Background: Epithelial ovarian cancer (EOC) is the most lethal cancer of the female reproductive system. In an earlier study, we identified multiple genes as hypermethylated in tumors of patients with poor prognosis. The most promising combination of markers to predict a patient’s outcome was CaMKIINα and RUNX3. Aim of this study was to functionally validate the importance of both genes. (2) Methods: IC50 measurements, cell cycle distribution-, proliferation, and migration experiments were conducted after transgene overexpression in two EOC cell lines. (3) Results: We showed that CaMKIINα has tumor suppressive functions in vitro and reduces proliferation, migration, and colony formation. However, it had no effect on the reversion of the resistance to cisplatin. RUNX3 exhibited dualistic functions related to cisplatin sensitivity and migration capacity, depending on the respective transcript variant (TV). A2780 cells expressing RUNX3 TV2—the promoter of which harbors a CpG (5′-C-phosphate-G-3′) island and is potentially inactivated by hypermethylation—exhibited increased cisplatin sensitivity and reduced migration properties. However, RUNX3 TV1, not affected by CpG island methylation could be characterized as mediating resistance and enhancing migration in A2780. The higher resistance of RUNX3 TV1 transfected cells correlates with a reduction of cell proliferation. Moreover, RUNX3 TV1 expressing cells exhibit a reduced cell cycle arrest at the gap-2 or mitosis phase (G2/M) under cisplatin treatment comparable to resistant A2780 subcultures. (4) Conclusion: It appears that CaMKIINα and RUNX3 TV2 can reduce the malignant potential of EOC cells

Platinum(ii) O,S complexes as potential metallodrugs against Cisplatin resistance

We report on platinum(ii) complexes with different cinnamic acid derivatives as ligands with cytotoxic activity against Cisplatin resistant ovarian cancer cell line subcultures of SKOV3 and A2780. A typical mechanism of action for platinum(ii) complexes as Cisplatin itself is binding to the DNA and inducing double-strand breaks. We examined the biological behavior of these potential drugs with 9-methylguanine using NMR spectroscopic methods and their DNA damage potential including γH2AX-foci analyses. X-ray diffraction methods have been used to elucidate the molecular structures of the platinum(ii) complexes. Interactions with the model protein lysozyme have been evaluated by different techniques including UV-Vis absorption spectroscopy, fluorescence and X-ray crystallography

The nuclear pore proteins Nup88/214 and T-cell acute lymphatic leukemia–associated NUP214 fusion proteins regulate Notch signaling

The Notch receptor is a key mediator of developmental programs and cell-fate decisions. Imbalanced Notch signaling leads to developmental disorders and cancer. To fully characterize the Notch signaling pathway and exploit it in novel therapeutic interventions, a comprehensive view on the regulation and requirements of Notch signaling is needed. Notch is regulated at different levels, ranging from ligand binding, stability to endocytosis. Using an array of different techniques, including reporter gene assays, immunocytochemistry, and ChIP-qPCR we show here, to the best of our knowledge for the first time, regulation of Notch signaling at the level of the nuclear pore. We found that the nuclear pore protein Nup214 (nucleoporin 214) and its interaction partner Nup88 negatively regulate Notch signalin