Non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, is characterized by low response rates and a poor prognosis. The majority of patients are diagnosed in advanced stages, where chemotherapy remains the gold standard of treatment. However, the resistance has been associated to cancer stem cells (CSCs), a highly tumorigenic subpopulation of cells with the ability to grow as spheres in non-adherent conditions. The aim of this study was to discover novel therapeutic strategies through screening platforms in order to target CSCs population.
High-throughput screening with commercial chemical libraries (Prestwick and Myria) was performed, comparing cytotoxic effect in monolayer cells vs. lung-tumorspheres derived from 8 resected NSCLC patients and 11 NSCLC cell lines. Compounds were added per triplicates at different concentrations (0.01 to 50 µM). Cell viability was measured after 48h using MTS Assay. Consecutively, 8 tumors were induced by inoculating resected NSCLC patient and H1650 lung-tumor-spheroids in NOD/SCID mice. Selected drugs were administered intraperitoneally (3 times a week, 100 mg/kg). Characterization of the inhibition pathway involved in the mechanism of action of these drugs was performed by RT-qPCR.
Three drugs of the commercial chemical libraries (DSF, Compound 1 and Compound 2) were identified with greater cytotoxic potential against lung tumorspheres, compared to a poor or null effect on monolayer cells. These results were validated in vivo, which demonstrated the capacity of these drugs to inhibit tumor growth in mice treated respect to the control (Table). We are currently characterizing the signaling pathways involved in the mechanism of action of these drugs.
Our findings reveal that these drugs can inhibit CSCs like properties, as evidenced in the lung tumorspheres in vitro and in vivo assays. Therefore, these compounds could be a promising targeted therapy as potential inhibitors of lung CSCs.Table: 1889P
Percentage of tumor reduction in the mice treated respect to the control
|Mice (Line/Patient)||Tumor Volume (mm3)||Tumor Reduction (%)|
|Patient Compound 1||721,56||56,16|
|Patient Compound 2||1020||38,02|
Clinical trial identification
Legal entity responsible for the study
Fundación para la Investigación Hospital General Universitario de Valencia.
Supported by ISCIII (P12-02838 / FIS P15-00573).
All authors have declared no conflicts of interest.