A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia.

Abstract

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasias but not in normal somatic tissues. Therefore, the telomerase complex represents a promising universal therapeutic target in cancer. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells. Telomere length was determined by either the terminal restriction fragment method or flow-FISH, and apoptosis was assessed by flow cytometry. Moreover, chemosensitivity was examined in telomestatin-treated U937 cells before ultimate telomere shortening. Treatment with telomestatin reproducibly inhibited telomerase activity in U937 and NB4 cells followed by telomere shortening. Enhanced chemosensitivity toward daunorubicin and cytosine-arabinoside was observed in telomestatin-treated U937 cells, before ultimate telomere shortening. Telomere shortening associated with apoptosis by telomestatin was evident in some freshly obtained leukemia cells from acute myeloid leukemia patients, regardless of sub-types of AML and post-myelodysplasia AML. These results suggest that disruption of telomere maintenance by telomestatin limits the cellular lifespan of AML cells, as well. However, in a minority of AML patients apoptosis was not evident, thus indicating that resistant mechanism might exist in some freshly obtained AML cells. Therefore, further investigation of telomestatin as a therapeutic agent is warranted.

• Authors: M Sumi, T Tauchi, G Sashida, A Nakajima, A Gotoh, K Shin-Ya, J H Ohyashiki, K Ohyashiki
• Journal: International journal of oncology (Int J Oncol) Vol. 24 Issue 6 Pg. 1481-7 (Jun 2004) ISSN: 1019-6439 [Print] Greece
• PMID: 15138591 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antimetabolites, Antineoplastic
• DNA-Binding Proteins
• Oxazoles
• telomestatin
• Cytarabine
• Telomerase
• Daunorubicin

Topics

• Acute Disease
• Aged
• Antibiotics, Antineoplastic (pharmacology)
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Cytarabine (pharmacology)
• DNA-Binding Proteins
• Daunorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Female
• Humans
• Leukemia, Myeloid (drug therapy, enzymology)
• Male
• Middle Aged
• Oxazoles (pharmacology)
• Telomerase (antagonists & inhibitors)
• Telomere (genetics, metabolism)
• U937 Cells (drug effects, metabolism, pathology)