ONCOLOGY LETTERS 3: 1159-1165, 2012
Abstract. Multiple myeloma (MM) is the second most
commonly diagnosed hematologic malignancy. Although new
drugs, including bortezomib and lenalidomide, have improved
the treatment landscape for MM patients, MM remains incur-
able. Therefore, screening for novel anti-myeloma drugs is
necessary. Gambogic acid (GA), the main active ingredient of
gamboges secreted from the Garcinia hanburryi tree, has been
reported to exhibit potent anticancer activity in certain solid
tumors and hematological malignancies, while there are few
studies that are available concerning its effects on MM cells.
In the present study, we investigated the anticancer activity
of GA on the MM RPMI-8226 cells and further studied the
underlying mechanisms by which GA affected the cells.
RPMI-8226 cells were cultured and the effect of GA on cell
proliferation was analyzed using MTT assay. Hoechst 33258
staining was used to visualize nuclear fragmentation, and
reactive oxygen species (ROS) levels were detected. GA was
found to have a significant, dose-dependent effect on growth
inhibition and apoptosis induction in RPMI-8226 cells. This
activity is associated with the accumulation of ROS, which
contributes to the activation of caspase-3 and the cleavage of
poly (ADP-ribose) polymerase (PARP), accompanied with
apoptosis in RPMI-8226 cells treated with GA. Mammalian
SIRT1, as the closest homolog of the yeast Sir2, was exten-
sively involved in regulating cell processes, including cell
senescence, aging and neuronal protection, as well as having
anti-apoptotic properties. Moreover, SIRT1 overexpression has
been shown to protect cancer cells from chemotherapy and
ionizing radiation. In the present study, we demonstrated that
GA has the potential to downregulate the expression of SIRT1
via ROS accumulation. In conclusion, our study found that
GA is able to induce apoptosis in RPMI-8226 cells via ROS
accumulation followed by caspase-3 activation, PARP cleavage
and SIRT1 downregulation. These results suggest that GA may
have the potential to not only induce apoptosis in MM cells,
but also to decrease the relapse rate of MM.
Multiple myeloma (MM) is the second most commonly diag-
nosed hematologic malignancy (1). Historically, the prognosis
of patients with MM has been poor due to a lack of effective
therapies. Over the past decade, although the introduction
of new drugs, including bortezomib and lenalidomide, has
improved the treatment landscape for MM patients, almost all
patients continue to experience disease relapse (2). Therefore,
further investigations to find a novel anti-myeloma drug should
Gambogic acid (GA, C38H44O8, Fig. 1) is the main
active ingredient of gamboges secreted from the Garcinia
hanburryi tree, which mainly grows in Southeast Asia. GA is
known to have extensive antitumor activities in certain solid
tumors (3,4). Over the last decade, our group has confirmed
that GA exhibits cytotoxicity in various types of hematological
malignancy (5,6). Various mechanisms by which GA exhibits
extensive anticancer activity have been reported, including
the downregulation of Bcl-2 (3,4), activation of p53 (7) and
caspase-3 (4) and the downregulation of the HERG potas-
sium channel (5). However, which point is the key target of
GA in the induction of the apoptosis of cancer cells remains
uncertain. As the changes in these proteins were correlated
with the generation of reactive oxygen species (ROS) (8-11), it
is suggested that GA contributes to ROS accumulation, which
causes changes in the proteins mentioned above as the down-
stream targets of ROS.
The molecular structure of GA includes an α,β-unsatured
ketone, which is present in certain drugs that induce apoptosis
by generating ROS (12) and ROS accumulation contributes to
the apoptosis of human hepatoma SMMC-7721 cells treated
Effects of gambogic acid on the activation of caspase-3
and downregulation of SIRT1 in RPMI-8226 multiple
myeloma cells via the accumulation of ROS
LI-JING YANG*, YAN CHEN*, JING HE, SHA YI, LU WEN, SHUAI ZHAO and GUO-HUI CUI
Department of Hematology, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, P.R. China
Received December 27, 2011; Accepted February 24, 2012
Correspondence to: Dr Guo-hui Cui, Department of Hematology,
Union Hospital, Tongji Medical College, Huazhong University of
Science and Technology, Jiefang Avenue 1277#, Wuhan 430022,
Key words: gambogic acid, reactive oxygen species, SIRT1,
ONCOLOGY LETTERS 3: 1159-1165, 2012
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