Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL‐R1 and TRAIL‐R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin‐ and bortezomib‐induced cell death

Abstract

Summary Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL‐R1, TRAIL‐R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti‐TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL‐R1 (HGS‐ETR1) and TRAIL‐R2 (HGS‐ETR2) this study demonstrated that both monoclonal antibodies activated caspase‐8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one‐thirds of the samples. HGS‐ETR1 and HGS‐ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase‐8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS‐ETR1 and HGS‐ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

“…A previous report showed that TRAIL-resistant THP-1 cells become sensitized to TRAIL-induced apoptosis when treated in combination with a phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor, perifosine [13]. Thus the cell-surface expression levels of DR4 and DR5 in leukemia cells are not strictly correlated with susceptibility to AY4-and TRAIL-induced cell death, in agreement with previous reports [11,28,36].…”

“…Doxorubicin, a DNA damaging agent, enhanced TRAIL-induced cell death of the Burkitt lymphoma cell line BJAB by facilitating DR5 clustering on the cell surface [10]. Doxorubicin also showed synergistic cytotoxicity with anti-DR4 agonistic mAb HGS-ETR1 and anti-DR5 agonistic mAb HGS-ETR2 in some primary and established lymphoma cells [11]. Likewise, etoposide and doxorubicin showed synergistic effects with TRAIL by selectively increasing DR5 expression, but not DR4 expression, in HL-60 and Jurkat cells [4].…”

“…1. The subtoxic dosages of each agent were very similar to those previously used in combination with TRAIL to induce synergistic cell death of various tumor cells [11,12,14,17,20,21,23]. The cells were treated for 24 h with subtoxic dosage of each chemical agent alone or in combination with either AY4 (10 lg/ml) or TRAIL (0.5 lg/ml) prior to the determination of cell viability.…”

“…Chemotherapeutic agents can counteract these resistance mechanisms by regulating downstream components in the extrinsic or intrinsic apoptotic pathways, which would enhance TRAIL-or anti-DR4/DR5 mAb-induced apoptosis of normally resistant tumor cells, including primary leukemia cells and established leukemia cell lines [2,3]. For example, subtoxic dosages of chemotherapeutic agents with different mechanisms of action, such as DNA damaging agents (doxorubicin and etoposide) [4,10,11], proteasome inhibitors (MG132) [12], phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor (perifosine) [13], and NFjB pathway inhibitor (SN50) [14,15], potentiated TRAILmediated cell death in various types of leukemia cells by modulating the extrinsic or intrinsic pathways. In particular, histone deacetylase inhibitors (HDACIs) have shown extensive synergistic cell death-inducing activity in combination with TRAIL [3,16].…”

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

“…In addition to the cognate ligand of recombinant TRAIL, several agonistic monoclonal antibodies (mAb) have been developed by targeting DR4 (7)(8)(9)(10) or DR5 (11)(12)(13)(14)(15)(16), which also induce cell death in various types of tumors in vitro and in vivo. Some of them are now under various phases of clinical trials (1)(2)(3)10).…”