1. ¹Felsenstein Medical Research Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Petah-Tikva, Israel
2. ²Institute of Oncology, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Petah-Tikva, Israel
3. ³Institute of Pathology, Assaf Harofeh Medical Center, Zerifin, Israel
4. ⁴Division of Infectious Diseases, Sheba Medical Center, Tel-Hashomer, Israel
5. ⁵Medicine A, Rabin Medical Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Petah-Tikva, Israel

Correspondence: Dr M Lahav, Department of Medicine A, Rabin Medical Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Petah-Tikva 49100, Israel. E-mail: mlahav@post.tau.ac.il

Received 18 January 2005; Revised 23 March 2005; Accepted 23 March 2005; Published online 3 May 2005.

Abstract

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 M IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.