Arsenic trioxide inhibits glioma cell growth through induction of telomerase displacement and telomere dysfunction

Abstract

Glioblastomas are resistant to many kinds of treatment, including chemotherapy, radiation and other adjuvant therapies. As2O3 reportedly induces ROS generation in cells, suggesting it may be able to induce telomerase suppression and telomere dysfunction in glioblastoma cells. We show here that As2O3 induces ROS generation as well as telomerase phosphorylation in U87, U251, SHG4 and C6 glioma cells. It also induces translocation of telomerase from the nucleus to the cytoplasm, thereby decreasing total telomerase activity. These effects of As2O3 trigger an extensive DNA damage response at the telomere, which includes up-regulation of ATM, ATR, 53BP1, γ-H2AX and Mer11, in parallel with telomere fusion and 3′-overhang degradation. This ultimately results in induction of p53- and p21-mediated cell apoptosis, G2/M cell cycle arrest and cellular senescence. These results provide new insight into the antitumor effects of As2O3 and can perhaps contribute to solving the problem of glioblastoma treatment resistance.

AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin

“…Immunofluorescence was performed as previously reported [17]. Cells were fixed in 2% formaldehyde and permeabilized in 0.25% Triton X100 in phosphate buffered saline (PBS) for 5 min at room temperature.…”

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

“…[30][31][32] It has been also reported that As 2 O 3 treatment leads to damage to telomeres. 33 We then studied whether Mus81 sumoylation was involved in DNA damage responses after exposure to metal toxins including arsenic and chromium . Consistent with an early report, 33 ATO exposure triggered DNA damage responses manifested as elevated levels of phosphorylated H2AX (g-H2AX) and phosphorylated ATM (p-ATM); however, cells expressing transfected His 6 -Mus81-5R plasmid displayed a reduced level of g-H2AX compared with cells transfected with the WT counterpart (Fig.…”

A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system

“…9,10 Interestingly, some studies have shown that ATO could also inhibit growth and induce apoptosis in a variety of solid tumor cells, such as breast, liver, gastric, prostate, renal, bladder, and glioma cells. [10][11][12][13][14] However, several limitations hinder its applications in clinical practice. The free ATO in aqueous solution exists as arsenite ions, with fast elimination in vivo, poor pharmacokinetics, and unacceptable systemic toxicity, including peripheral neuropathies and liver failure.…”