Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 70
Cytotoxicity of TRAIL/anticancer agent combinations in human primary cells
Olivier Meurette1, Anne Fontaine1, Amélie Rebillard1, Thierry Lamy2, Dominique
Lagadic-Gossmann1 and Marie-Thérèse Dimanche-Boitrel1
1 INSERM Unit 620, University of Rennes 1, Faculty of Pharmacy, 2 Av du Pr. Leon
Bernard 35043 Rennes cedex France; 2 Department of Hematology, Pontchaillou
Hospital, Rennes, France.
TRAIL (TNF-"-Related Apoptosis Inducing Ligand) is a potential anticancer agent that
induces apoptosis by binding to its death receptors TRAIL-R1 and/or -R2 in cancer cells but
not in most normal cells. TRAIL also possesses two decoy receptors (TRAIL-R3/-R4). Some
cancer cells are resistant to TRAIL-induced apoptosis. Combining TRAIL with a wide range
of anticancer agents can restore cancer cell sensitivity to cell death, and combination of
TRAIL with anticancer drugs is now tested in clinical trials. At present, the cytotoxic effect of
such combinations in normal human primary cells is not well known.
We studied here the sensitivity of several human primary cells: hepatocytes, lymphocytes and
neutrophils to combination of TRAIL with cisplatin or 5-fluorouracil in relation with TRAIL
receptors membrane expression. We show that human primary hepatocytes express
exclusively TRAIL-R4 decoy receptor on the cell membrane. In contrast to Fas ligand,
TRAIL is not cytotoxic towards human primary hepatocytes. However, these normal cells
become only sensitive to TRAIL/cisplatin but not to TRAIL/5-fluorouracil. Cisplatin or 5fluorouracil
treatment has no effect on TRAIL receptors membrane expression in human
primary hepatocytes. Freshly isolated lymphocytes express solely TRAIL-R4 at the cell
membrane and are resistant to TRAIL. However, as human hepatocytes, lymphocytes are only
sensitive to TRAIL/cisplatin and resistant to TRAIL/5-fluorouracil. Interestingly, these both
combinations are cytotoxic towards PHA+IL-2 activated lymphocytes which express a little
amount of TRAIL-R1 and TRAIL-R2 on the cell membrane. Finally, freshly isolated
neutrophils express exclusively TRAIL-R3 on the plasma membrane and are resistant to
TRAIL and to TRAIL/anticancer agent combinations.
Altogether, these data demonstrate that human primary cells express exclusively TRAIL
decoy receptors (TRAIL-R3 or TRAIL-R4) and are resistant to TRAIL. However, the
cytotoxicity of certain TRAIL/anticancer drugs combinations towards human primary cells
should be taken into account for the development of TRAIL-based anticancer therapy.
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