is associated with activation of NF-κB-induced antiapoptotic target genes (Altucci et
al., 2001). Since the majority of patients with APL are resistant to ATRA, and
complete remission induced by ATRA is followed by the emergence of ATRA-
resistant disease, it will be interesting to determine whether ATRA-resistant APL cells
can be treated by inhibition of NF-κB and/or administration of Apo2L/TRAIL.
7.3
Targeting death receptors for treatment of cancersGenetic aberrations that render cells resistant to diverse chemotherapeutic agents or
ionizing radiation, such as loss of the p53 tumor suppressor gene or overexpression
of Bcl-2, underlie the observed resistance of human cancers to conventional anticancer
therapy (Kaufmann and Earnshaw, 2000). Identifying approaches to induce apoptosis
in tumors that harbor such genetic impediments could lead to effective therapeutic
interventions against resistant human cancers. Since death receptors provide an
alternative mechanism of activating caspases and triggering cell death, ligand- or
antibody-induced engagement of death receptors may be an attractive strategy for
anticancer therapy. However, the clinical utility and therapeutic ratio of this approach
depends on the differential sensitivity of tumor cells and normal tissues to each agent
and/or the ability to target delivery of death ligands/antibodies to tumor cells.
Although TNF-α and CD95L can induce apoptosis of several types of tumor cells
in vitro, their clinical application in cancer therapy is hindered by the serious toxicity
of these ligands in vivo. Systemic administration of TNF-α causes a serious
inflammatory septic shock-like syndrome that is induced by NF-κB-mediated
expression of proinflammatory genes in macrophages and T cells. Systemic
administration of FasL or agonistic antibodies against CD95 causes lethal hepatic
apoptosis. In contrast to these ligands, Apo2L/TRAIL holds enormous promise for
anticancer therapy.
A broad spectrum of human cancer cell lines express death receptors for Apo2L/
TRAIL (TRAIL-R1/DR4 and TRAIL-R2/DR5) and exhibit variable sensitivity to
Apo2L/TRAIL-induced apoptosis (Ashkenazi et al., 1999). Although Bcl-2 protects
cells from diverse cytotoxic insults, Bcl-2 overexpression does not confer significant
protection against induction of apoptosis by Apo2L/TRAIL (Ravi et al., 2001).
Likewise, tumor cells that resist DNA damage-induced apoptosis by virtue of loss of
p53 also remain susceptible to induction of apoptosis by TRAIL/Apo2L. Cancer cells
with wild-type p53 (p53+/+) and their isogenic p53-/- derivatives generated by deletion
of p53 via targeted homologous recombination are equally sensitive to TRAIL/
Apo2L-induced apoptosis (Ravi and Bedi, 2002). The tumoricidal activity of Apo2L/
TRAIL in vivo has been confirmed in preclinical animal models (athymic nude or
SCID mice) carrying human tumor xenografts without any evidence of toxicity to
normal tissues (Ashkenazi et al., 1999; Roth et al., 1999; Walczak et al., 1999). Apo2L/
TRAIL prevented the growth of evolving breast or colon or glial cancers after
xenotransplantation, and decreased the size of established tumors. More importantly,
systemic treatment with Apo2L/TRAIL significantly improved the survival of tumor-
DEATH RECEPTORS IN APOPTOSIS 29