Novel nucleoside derivatives for effective ovarian cancer stem cells treatment

J. Ma1, M. Rabbani1, L. Peng2, A. Wong1. 1School of Biological Sciences, The University of Hong Kong, Hong Kong, HONG KONG, 2Axi-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, Marseille, FRANCE

Introduction: Ovarian cancer is the most lethal of all gynecologic cancers with high rate of deaths. The current therapy is effective for patients with early stage, however most patients were at advanced stage when diagnosis. Ovarian cancer stem cells (OCSCs) present in malignant ascites of patient with advanced ovarian cancer represent a major impediment to effective treatment1. Nucleosides are known to be promising anti-viral, anti-cancer and anti-bacterial drug candidates. Nucleoside analogs were reported to demonstrate apoptosis-related anticancer effects2. In this study, we aim to develop novel nucleoside derivatives against OCSCs.

Methods: 26 nucleoside derivatives were synthesized and screened for the anti-OCSCs activity. OCSCs were cultured as previous described1 and then treated with nucleoside derivatives for 48 h at different concentrations (0 nM, 5 nM, 50 nM, 500 nM, 5 μM, and 50 μM). OCSCs were collected and cell viability was measured by MTT assay. IC50 values were calculated by SPSS software. Cisplatin and imatinib were served as positive controls. The anti-cancer activity (IC50 values) of these nucleoside derivatives were also measured in ovarian non-cancer stem cells (non-OCSCs). The potential signaling pathway were investigated by real-time RT-PCR. Data were expressed as mean±sd (n=6) and analysis was performed using one-way ANOVA followed by Tukey test.

Results: These nucleoside derivatives showed stronger anti-tumor activity towards OCSCs than non-OCSCs. Cisplatin was more sensitive to non-OCSCs, and imatinib was more sensitive to OCSCs (IC50 ~20 nM). Of all the 26 nucleoside derivatives, 8 compounds showed very significant anti-OCSCs activity with IC50 values lower than 100 nM (The lowest IC50 values can reach 7.5 nM); 11 compounds present with IC50 values between 100 nM to 1 μM; 7 compunds showed less significant anti-OCSCs activity with IC50 values greater than 1 μM. Heat shock protein 27 (Hsp27) and c-kit may involve in the mechanisms of more sensitive to OCSCs than non-OCSCs of these nucleoside derivatives.

Conclusion: These nucleoside derivatives showed different anti-OCSCs and anti-non-OCSCs activity. The compounds with very significant anti-OCSCs activity will be screened for further in vitro and in vivo study.

References:

1. Ip CKM et al. (2014). Oncotarget 5: 9133-9149.

2. Xia Y et al. (2009). J Med Chem 52: 6083-6096.