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-(ADP-ribose) 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 dominant-negative 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 DN-hTERT-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 
telomestatin-treated 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.