[Cancer Biology & Therapy 7:4, 603-608; April 2008]; ©2008 Landes Bioscience
Bortezomib (VELCADE®), formerly known as PS-341, is a
novel dipeptide boronic acid proteasome inhibitor with in vitro
and in vivo anti-tumor activity. Bortezomib has been approved for
the treatment of multiple myeloma and mantle cell lymphoma.
In this report, we examined the sensitivity of cell lines derived
from Ewing’s sarcoma-family of tumors (ESFT) to Bortezomib.
Five ESFT-derived cell lines, TC-71, TC-32, SK-N-MC, A4573
and GRIMES, were highly sensitive to Bortezomib (IC50 = 20 to
50 nM), and underwent cell cycle arrest and apoptosis following
drug treatment. Bortezomib-induced apoptosis was associated with
activation of caspase 3, cleavage of PARP and induction of p27
and p21 expression. Moreover, Bortezomib exhibited synergistic
activity against the TC-71 and TC-32 cell lines when combined
with TRAIL. Our results suggest that Bortezomib might be a
useful agent for treatment of ESFT, when used alone or in combi-
nation with TRAIL.
Ewing’s sarcoma family of tumors (ESFT), which include Ewing’s
sarcoma (ES), Askin’s tumor and primitive neuroectodermal tumors
(PNET), arise in bone and soft tissue. They account for 10–15% of
all primary bone tumors and are the second most common malignant
bone tumors occurring in children and young adults.1 Histologically,
ESFT present as small blue round cell tumors with weak neural
differentiation. These tumors are usually associated with a t(11;22)
(q24;q12) chromosomal translocation, which results in the produc-
tion of the EWS-FLI1 fusion protein, a chimeric transcription factor
with oncogenic properties.2 ESFT present with localized disease
in approximately 75% of patients and local therapy, consisting of
surgery and radiotherapy combined with systemic chemotherapy
is able to achieve a 70% cure rate.3 In contrast, the prognosis of
patients with metastases or early relapse remains extremely poor (cure
rates below 25%) despite intensive chemo- and radiation-therapy,
including administration of high dose chemotherapy followed by
stem cell transplantation.3 Moreover, the outcome of patients with
advanced disease has not substantially changed over the last two
decades.3 Thus, there is an urgent need for more effective therapies
for the treatment of these tumors.
Proteasome is a multi-catalytic proteinase complex responsible
for the degradation of most intracellular proteins, including proteins
crucial to cell cycle regulation and apoptosis.4 Bortezomib is a selec-
tive inhibitor of the 26S proteasome and has been approved by
the U.S. Food and Drug Administration for treatment of multiple
myeloma and mantle cell lymphoma.4 Preclinical and early clinical
data suggest that Bortezomib also has significant anti-tumor activity
against several solid tumors, including prostate cancer, ovarian cancer
and squamous cell cancer of the head and neck.4-6
Apo2 ligand (Apo2L) or tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL) is one of the members of the
TNF gene superfamily that induce apoptosis through engagement
of its receptors Death receptors 4 and 5 and is currently in clinical
trials for treatment of human malignancies.7 We and others have
previously reported that ESFT-derived cell lines express the TRAIL
receptors and are generally sensitive to TRAIL/Apo2L induced
In this report, we have examined the effect of Bortezomib, when
used alone or in combination with TRAIL/Apo2L, against a group of
five ESFT-derived cell lines. We report that Bortezomib is cytotoxic
to these ESFT-derived cell lines and has a synergistic apoptotic effect
when combined with TRAIL/Apo2L.
Bortezomib inhibits cell proliferation and reduces viability
in ESFT cell lines. We examined the effect of Bortezomib on the
viability of five cell lines (TC-71, TC-32, GRIMES, SK-N-MC
and A4573) derived from the ES family of tumors. For comparison,
we included the H460 cell line, which is derived from a human
Proteasome inhibitor Bortezomib induces cell cycle arrest and
apoptosis in cell lines derived from Ewing’s sarcoma family
of tumors and synergizes with TRAIL
Guangrong Lu,1 Vasu Punj2 and Preet M. Chaudhary1,2,*
1Hamon Center for Therapeutic Oncology Research; University of Texas Southwestern Medical Center; Dallas, Texas USA; 2Department of Medicine and University of Pittsburgh
Cancer Institute; Pittsburgh, Pennsylvania USA
Abbreviations: TRAIL, TNF-related apoptosis inducing ligand; Apo2L, Apo2 ligand; ESFT, Ewing’s sarcoma family of tumors
Key words: Ewing’s sarcoma, Bortezomib (PS-341), apoptosis, TRAIL
*Correspondence to: Preet M. Chaudhary; Hillman Cancer Center; 5117 Centre
Avenue; Suite 1.19A; Pittsburgh, Pennsylvania 15213-1863 USA; Tel.: 412.623.7703;
Fax: 412.623.1415; Email: firstname.lastname@example.org
Submitted: 12/19/07; Revised: 01/11/08; Accepted: 01/11/08
Previously published online as a Cancer Biology & Therapy E-publication:
www.landesbioscience.comCancer Biology & Therapy603
Effect of Bortezomib on Ewing’s sarcoma family of tumors
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