Effects of in vitro short- and long-term treatment with telomerase inhibitor in U-251 glioma cells

Abstract

BACKGROUND: The inhibition of the enzyme telomerase (TERT) has been widely investigated as a new pharmacological approach for cancer treatment, but its real potential and the biochemical consequences are not totally understood. OBJECTIVE: Here, we investigated the effects of the telomerase inhibitor MST-312 on a human glioma cell line after both short- and long-term (290 days) treatments. METHODS: Effects on cell growth, viability, cell cycle, morphology, cell death and genes expression were assessed. RESULTS: We found that short-term treatment promoted cell cycle arrest followed by apoptosis. Importantly, cells with telomerase knock-down revealed that the toxic effects of MST-312 are partially TERT dependent. In contrast, although the long-term treatment decreased cell proliferation at first, it also caused adaptations potentially related to treatment resistance and tumor aggressiveness after long time of exposition. CONCLUSIONS: Despite the short-term effects of telomerase inhibition not being due to telomere erosion, they are at least partially related to the enzyme inhibition, which may represent an important strategy to pave the way for tumor growth control, especially through modulation of the non-canonical functions of telomerase. On the other hand, long-term exposure to the inhibitor had the potential to induce cell adaptations with possible negative clinical implications.

The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases

“…Interestingly, several telomere or telomerase-targeting treatments have shown effect on tumor cell lines or animal models without affecting telomere length. After short-term treatment with the telomerase inhibitor MST-312, glioma cell lines undergo cell cycle arrest and apoptosis but subsequent adaptations after long-term treatment lead to increased aggressiveness [ 92 ]. MST-312 has also been shown to reduce pediatric ependymoma cell populations harvested from surgical specimens [ 93 ].…”