Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia

Abstract

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines. In the present study, we investigated the mechanisms of apoptosis induced by telomerase inhibition in acute leukemia. We have found the activation of caspase-3 and poly-(ADPribose) polymerase in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25). Activation of p38 mitogen-activated protein (MAP) kinase and MKK3/6 was also found in telomestatin-treated U937 cells (PD20) and dominantnegative DN-hTERT-expressing U937 cells (PD25); however, activation of JNK and ASK1 was not detected in these cells. To examine the effect of p38 MAP kinase inhibition on growth properties and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing U937 cells with or without SB203580. Dominant-negative-hTERT-expressing U937 cells stopped proliferation on PD25; however, a significant increase in growth rate was observed in the presence of SB203580. Treatment of SB203580 also reduced the induction of apoptosis in DNhTERT-expressing U937 cells (PD25). These results suggest that p38 MAP kinase has a critical role for the induction of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the effect of telomestatin on the growth of U937 cells in xenograft mouse model. Systemic intraperitoneal administration of telomestatin in U937 xenografts decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from telomestatintreated animals exhibited marked apoptosis. None of the mice treated with telomestatin displayed any signs of toxicity. Taken together, these results lay the foundations for a program of drug development to achieve the dual aims of efficacy and selectivity in vivo.

Modulation of Telomerase Activity and Human Telomerase Reverse Transcriptase Expression by Caspases and Bcl-2 Family Proteins in Cisplatin-Induced Cell Death

“…In an effort to identify the modulators of telomerase in the progression of cancers, we utilized a cisplatin-induced Currently, in order to inhibit telomerase, a variety of strategies have been adopted, including the introduction of TERT antisense oligomer [19,20], G-quadruplex-interactive agents [21,22], or small interference RNA [23]. In this study, we hypothesized that the targeting of the signaling modulators of telomerase might induce apoptosis in cancer cells.…”

Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer

“…In this regard, growing evidence shows that G4 ligands selectively impair the growth of cancer cells without affecting the viability of normal cells pointing out these molecules as possible drug candidates for future clinical application (8,9). This evidence gains further support by the marked antitumoral activity showed by some of those compounds (BRACO-19, RHPS4, and telomestatin) in different in vivo models both as single agents and in combination with conventional or targeted anticancer agents (10)(11)(12)(13)(14)(15). However, none of the other G4 ligands developed so far has made it through the drug discovery pipeline due to poor drug-like properties and/or selectivity profile (16,17).…”

Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors

“…Overexpression of telomerase has been demonstrated in 85-90% of human tumor cells but not at all in the majority of human normal somatic cells (38). Therefore, inhibiting telomerase may be a promising therapeutic strategy for the treatment of different types of cancer (10).…”