Leukemic stem- and progenitor cells exhibit low cycling activity which might represent a major cause for their increased treatment resistance. TRAIL (TNF-related apoptosis inducing ligand) is a novel putative anticancer drug currently in phase I and II clinical testing. We recently showed that TRAIL is able to address stem- and progenitor cells from patients with acute lymphoblastic leukemia (ALL) in xenotransplantation assays (Alves et al., Blood 2012,119,4224). As stem- and progenitor cells are often non-cycling, we asked here, whether TRAIL is able to address resting leukemia cells.
We used cell lines and primary tumor cells from children with ALL which were amplified in severely immuno-compromised mice (NSG mice). Cell cycle arrest was induced (i) by addition of conventional cytotoxic drugs which are known to act as cytostatic drugs such as doxorubicine; (ii) by biochemical inhibitors known to induce cell cycle arrest at different defined points of the cell cycle such as mimosine; (iii) by molecular approaches and knockdown of cyclinB arresting cell cycle in G2 or knockdown of cyclinE arresting cell cycle in G1.
Unexpectedly, TRAIL-induced apoptosis was enhanced, whenever cell cycle was arrested. Cell cycle arrest sensitized towards TRAIL-induced apoptosis independently from the point or phase of cell cycle which was arrested (G0, G1 or G2) and independently from the agent used to arrest the cell cycle. Similarly, knockdown of cyclinB or cyclinE both clearly sensitized cell line cells towards TRAIL-induced apoptosis.
Cytotoxic drugs and cell cycle inhibitors might arrest the cell cycle by activation of p53. Accordingly, when caffeine was added which inhibited p53 activity and drug-induced cell cycle arrest, sensitization towards TRAIL-induced apoptosis was blocked.
We have recently established a novel method which enables performing knockdown experiments in tumor cells derived from ALL patients (Höfig et al., Cell Comm. Signal. 2012,10,8). Using this method and most important for clinical translation, we could show that knockdown of either cyclinB or cyclinE clearly sensitized patient-derived ALL cells towards TRAIL-induced apoptosis.
Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts anti-tumor activity preferentially against tumor cells in cell cycle arrest and less against actively cycling tumor cells. This special feature of TRAIL might explain its anti-tumor activity against stem- and progenitor cells in patients with ALL. Thus, TRAIL might represent an interesting drug to treat disease stages with accumulation of stem- and progenitor cells and static tumor disease, e.g., during minimal residual disease.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.