Targeted inhibition of telomerase activity combined with chemotherapy demonstrates synergy in eliminating ovarian cancer spheroid-forming cells

Objective: Telomerase activity (TA) is often used as a molecular marker for Cancer aggressiveness. Our objectives were to determine the TA in ovarian Cancer cell lines and the effectiveness of targeting Telomerase for Cancer therapy.

Methods: Ovarian Cancer cell lines of various histologic subtypes were chosen to correspond to decreasing levels of clinical aggressiveness. Cells were grown in non-adherent growth conditions to form spheroid-forming cells (SFC). Telomerase activity was quantified using the TRAPeze RT Telomerase Detection Kit and confirmed with luciferase reporter plasmid containing promoter of human telomerase Reverse Transcriptase (hTERT). Cell proliferation survival assays were performed after treatment with a small molecule Telomerase Inhibitor BIBR1532 both with and without multiple chemotherapeutic agents.

Results: Compared to monolayer, TA from SFC correlated to the innate clinical aggressiveness of ovarian Cancer cell lines ES2, SKOV3, and TOV112D. Treatment with BIBR1532 resulted in up to a 12-fold decrease in TA compared to controls. SFCs were significantly more resistant to BIBR1532 compared to monolayer cell lines; however, it showed reasonable efficacy at 100 uM. In combination assays, the addition of BIBR1532 to carboplatin yielded the most favorable results in regards to synergy in all three cell lines evaluated.

Conclusions: Telomerase activity appears to correlate to the clinical aggressiveness seen in histologic subtypes of ovarian Cancer. BIBR1532 demonstrated significant inhibition of TA as well as reasonable efficacy as a single agent. Inhibition of Telomerase with BIBR1532 in combination with carboplatin demonstrated a more than additive effect in-vitro and could represent a novel targeted therapy for ovarian Cancer.