Telomerase inhibition enhances apoptosis in human acute leukemia cells: possibility of antitelomerase therapy

Abstract

Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. We examined the impact of telomerase inhibition by the dominant-negative human catalytic subunit of telomerase (DN-hTERT) on the biological features of acute leukemia. We introduced vectors encoding dominant-negative (DN)-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistant marker into a telomerase-positive human acute lymphoblastic leukemia cell line, HAL-01. Expression of DNhTERT dramatically inhibited telomerase activity, leading to apoptotic cell death. Mutant telomerase expression also enhanced daunorubicin-induced apoptosis. Nude mice (n = 5 per group) received subcutanous implants of HAL-01 cells expressing the control vector or DN-hTERT or WT-hTERT. Implantation of HAL-01 cells expressing control vector (n = 5) rapidly produced tumors, whereas implantation of those expressing DN-hTERT (n = 5) did not. Thus, telomerase inhibition both growth of HAL-01 cells in vitro and tumorigenic capacity in vivo. Furthermore, the G-quadruplex-interactive telomerase-specific inhibitor, telomestatin, shortened the telomere length and induced apoptosis in freshly isolated primary acute leukemia cells. These results suggest that antitelomerase therapy may be useful in some acute leukemias in combination with antileukemic agents such as daunorubicin.

Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands

“…Consistent with such a mechanism of action, we showed that active pyridine derivatives required several rounds of replication (3-7 depending on the cell line) to induce cell growth arrest even when these compounds were used at high concentrations. Moreover, the active pyridine derivatives induced cell death in the glioma cell lines within delays (1-3 weeks depending on drug concentration) similar to that observed by direct inhibition of telomerase activity in cell lines with short telomeres in other studies (Hahn et al, 1999;Zhang et al, 1999;Nakajima et al, 2003).…”

Telomerase is limiting the growth of acute myeloid leukemia cells

“…The value of telomerase inhibition in leukemia treatment needs to be established in clinical trials in combination with standard antileukemic agents. 42,54,55 …”

Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo

“…Although a variety of telomerase inhibitors have been shown to inhibit proliferation of cancer cells, [18][19][20][21][22][23][24][25][27][28][29] there has been a need of agents which are specific enough and suited for in vivo utilization in human clinical trials. Our telomerase inhibitor (GRN163L) is phosphoramidate oligonucleotide complementary to the template region of the RNA subunit of telomerase (hTR) and has a lipid moiety attached, which facilitates uptake in human cells without any need of a transfection reagent or procedure.…”

“…A number of telomerase inhibitors have been evaluated in a variety of cancer types. [19][20][21][22][23] We have demonstrated that telomerase inhibitors including G-quadruplex interacting agents, 18,24,25 peptide nucleic acids and antisense oligonucleotides targeting RNA component of telomerase, [26][27][28] and siRNAs targetinghTERT, 29 can induce apoptosis and/or senescence in a variety of human immortal and cancer cells including multiple myeloma cells, in vitro.…”