Development of molcular target therapy for.... telomerase

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The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Genetic experiments using a dominant-negative form of human telomerase have demonstrated that telomerase inhibition can result in telomere shortening followed by proliferation arrest and cell death by apoptosis (Tauchi et al. Chin Cancer Res, 8; 3341, 2002).Recently, we have demonstrated that treatment with telomestatin (SOT-095) reproducibly inhibited telomerase activity in the BCR-ABL positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 μM, however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34 positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21^<CIP1> and p27^<KIP1>. Telomestatin also activated MKX3/6 and p38MAP kinae and induced apoptosis by caspase-3 cascades. These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response and MKK3/6-p38MAP kinase cascade. We conclude that telomerase inhibitors combined use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.