In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3326-3326
Abstract:
Resting tumor cells represent a huge challenge during anti-cancer therapy due to their increased treatment resistance. Example given, during minimal residual disease remaining tumor cells might be non-cycling. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anti-cancer drug currently in phase I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates (Blood 2012,119,4224). Here we tested the ability of TRAIL to target cell cycle arrested tumor cells. Primary tumor cells from children with acute lymphoblastic leukemia were amplified in immuno-compromised mice and used for in vitro knockdown studies, besides tumor cell lines. Cell cycle arrest was induced in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Cell cycle was visualized by flowcytometry analysis including phosphorylation of Serine 10 in Histone H3 to discriminate G2 from M phase. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis, independently from the tumor cell type, the cell cycle inhibitor used or the check point addressed. In contrast, when cell cycle arrest was disabled by addition of caffeine, the anti-tumor activity of TRAIL was reduced. Most importantly for clinical translation, tumor cells from three children with B-precursor or T-cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced anti-tumor activity against cell cycle arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static tumor disease, e.g., during minimal residual disease. Citation Format: Harald Ehrhardt, Franziska Wachter, Michaela Grunert, Irmela Jeremias. TRAIL induces apoptosis preferentially in cell cycle arrested tumor cells, e.g., in tumor cells from children with acute lymphoblastic leukemia upon knockdown of cyclinE. [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3326. doi:10.1158/1538-7445.AM2013-3326 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3326
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
