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Cancer Letters 292 (2010) 149–152
Contents lists available at ScienceDirect
Cancer Letters
journal homepage: www.elsevier.com/locate/canlet
Mini-review
RNA polymerase – An important molecular target of triptolide in
cancer cells
Jingxuan Pan *
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, People’s Republic of China
a r t i c l e
i n f o
Article history:
Received 5 November 2009
Received in revised form 26 November 2009
Accepted 27 November 2009
Keywords:
Triptolide
RNA polymerase
Molecular target
Cancer
a b s t r a c t
Triptolide, a diterpenoid triepoxide, is the key biological component of Tripterygium wilfordii Hook. f. which was used in traditional Chinese medicine for centuries to treat inflammation and autoimmune diseases. Triptolide has shown potent activity in not only antiinflammation and immune modulation, but also antiproliferative and proapoptotic activity
in many different types of cancer cells. However, for a long time, the precise molecular target(s) of triptolide have remained elusive. Recently, several groups discovered that triptolide inhibited the activity of RNA polymerase. This review will focus on these breakthrough
findings about the molecular target of triptolide and its implications for targeted-cancer
therapeutics.
Ó 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Traditional Chinese medicine has used Tripterygium wilfordii Hook. f. for centuries to treat inflammation and autoimmune diseases [1–4]. Among the many small molecules
extracted and purified from this shrub-like vine, triptolide
is the key biologically active component that mediates
immunosuppression and anti-inflammation, and antineoplastic effect [3,5]. Triptolide has been shown antiproliferative and proapoptotic activity in a broad spectrum of
cancer cells (Table 1). Although the precise molecular targets remain elusive, recent studies in cancer cells have revealed that RNA polymerase may be an important target of
triptolide. This review will focus on the inhibitory effect of
triptolide on the RNA polymerase and its implications for
targeted-cancer therapeutics.
2. Triptolide inhibits growth of tumor cells at
nanomolar concentrations
Triptolide was first characterized as a diterpenoid triepoxide lactone containing an 18 (4f3) abeo-abietane skele* Tel./fax: +86 20 87332788.
E-mail address: [email protected]
0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2009.11.018
ton in 1972 [6]. Since then, a large body of literature has
demonstrated that triptolide at low concentrations inhibits
growth of different types of cancer cells including hematologic malignancy and solid tumor cells. The IC50 values
were listed in Table 1.
In addition, triptolide potentiates the activities of other
chemotherapeutic agents and therefore may be useful not
only as a monotherapy but also in combination with other
cytotoxic drugs for cancer treatment. For instance, triptolide enhances the bortezomib-induced apoptosis in
multiple myeloma cells by inactivating PI3 K/Akt/NF-jB
pathways [17]. It also sensitizes tumor cells to apoptosis
stimuli such as Apo2/TRAIL, tumor necrosis factor a, and
various chemotherapeutic agents [10,17–19]. Of note, triptolide was effective against tumor cells that overexpress
the MDR1 and are resistant to the effects of other chemotherapeutic compounds (e.g., paclitaxel) [20].
3. Mechanism of triptolide to inhibit growth of tumor
cells
Since its discovery in 1972, triptolide with its unique
chemical structure attracts numerous scientists to elucidate
its pharmacological mechanisms. Early studies emphasized
the inhibitory effect of triptolide on NF-jB activation since
150
J. Pan / Cancer Letters 292 (2010) 149–152
Table 1
IC50 values of triptolide in tumor cells.
Tumor type
Cell lines
IC50
(nM)
References
Chronic myelogenous
leukemia (CML)
KBM5
6.1
[7]
KBM5-T315I
BaF3-Bcr-Abl
BaF3-T315I
K562
Primary blast
cells
(imatinibresistant)
U937
5.5
6.5
5.4
5.7
4.8–
13.3
[7]
[7]
[7]
[7]
[7]
6.5
[8]
Molt-4
HL-60
HEL
Primary blast
cells
SMMC
Jurkat
17
7.5
2.6
15.5–
47.8
32
27.5
[9]
[10]
[11]
[12]
[10]
[10]
Raji
25.08
[13]
Namalwa
RPMI8226
NCI-H929
U266
HCT-15
HCT-116
SW1116
Lovo
HT29
Lsd174T
SMMC-7721
BEL-7402
Miapaca2
BxPC3
SGC-7901
MKN-28
MDA-MB-231
MX1
MCF-7
SK-OV-3
HO-8910
PC-3
DU-145
786-O
KB
10
69.4
4.8
72.2
29
10
52
77
2.8
3.5
18
20
5.2
20
15
200
24
3.2
19
10
28
43
24
22
43
[8]
[14]
[8]
[14]
[9]
[9]
[9]
[8]
[15]
[8]
[9]
[9]
[8]
[8]
[9]
[9]
[9]
[8]
[9]
[9]
[9]
[9]
[9]
[9]
[9]
OEC-M1
SCC25
KB
3.56
3.75
4.13
[16]
[16]
[16]
Rh30
HeLa
U251
14
47
49
[9]
[9]
[9]
Acute myeloid
leukemia (AML)
Acute lymphoid
leukemia (ALL)
Non-Hodgkin’s
lymphoma
Lymphoma
Mutiple myeloma
Colon cancer
Liver cancer
Pancreatic cancer
Stomach cancer
Breast cancer
Ovarian cancer
Prostate cancer
Kidney cancer
Oral squamous cell
carcinoma
Oral epidermoid carcinoma
Tongue squamous cancer
Gingival epidermoid
carcinoma
Rhabdomyosarcoma
Cervix cancer
Neurogliocytoma
the latter is critical for both inflammation and tumorigenesis [14,21,22]. However, the spectrum of genes suppressed
by triptolide is much larger and beyond the gene spectrum
controlled by NF-jB [8]. Vispe et al. examined the effect of
triptolide on gene expression with a whole human genomic
DNA microarrays containing 45,015 probes, and discovered
that a 4-h treatment with triptolide (0.45 lM) led to upregulation of 160 genes and downregulation of 1511 in nonsmall cell lung cancer cell line A549 [8]. Du et al. reported
the underexpression of 117 genes in triptolide-treated leu-
kemia Jurkat cells [23]. Independently, we reported that triptolide repressed the expression of Bcr-Abl, KIT, PDGFRa,
and Jak2, respectively [7,11,24,25]. Apoptosis related proteins such as XIAP, Bcl-2, Mcl-1, and the cell cycle regulators
CDC25A, Polo-like kinases Plk2, Plk3, and Plk4 were significantly suppressed by triptolide [19,20,26]. Heat shock protein 90 and Heat shock protein 70 were also decreased by
triptolide [27]. Moreover, triptolide suppresses the transactivation of general transcription factors [e.g., AP-1 (activator
prtein-1), NFAT and HSF1 (heat shock factor 1), TAFs, TBP,
CEBPA-CEBPB, myc, fos, SP1, Jun B] and specific transcription factors (ZNFs, NRF1, NFYA, and HSF2) [8]. Therefore, it
is impossible to explain the suppression of such a broad
range of genes by triptolide treatment simply by inactivation of NF-jB pathway.
McCallum et al. showed that triptolide inhibits de novo
total RNA transcription in A549 and THP-1 tumor cells
[28]. Leuenroth and Crews demonstrated that triptolideinduced nuclear speckle rounding indicating mRNA splicing had ceased, and normal nucleolar structure also disappeared [29]. The nuclear substructural changes are
associated with a decrease in RNA polymerase II (RNA Pol
II) COOH-terminal domain Ser2 phosphorylation. After
RNA Pol II inhibition, RNA Pol I transcriptional activity is
also attenuated, affecting RNA ribosome biogenesis. Therefore, Leuenroth and Crews remarked that triptolide suppresses global transcription in a concentration-dependent
manner. Independently, we demonstrated that triptolide
decreases the activity of RNA Pol II in different leukemia
cells (e.g., KBM5, HMC-1, EOL-1 and HEL cells) [7,11,24,25].
Recently, Vispe et al. measured the effect of triptolide
on the RNA synthesis by using [H3]uridine incorporation,
and found that triptolide inhibits both total RNA and
mRNA neosynthesis by up to 80% [8]. However, triptolide
is not a DNA binder; an in vitro transcription assay did
not support that triptolide have the ability to directly
interact and inhibit the elongating RNA polymerase II complex. Despite so, it can not be ruled out a possibility that
the reconstituted in vitro assay did not completely reflect
the in vivo RNA polymerase II complex. Vispe et al. discovered that RPB1, the catalytic and the largest RNA polymerase II main subunit, was shown downregulated by 2-h
treatment of triptolide; this effect was further amplified
with longer incubation times up to 16 h [8]. The presence
of proteasome inhibitors (i.e., bortezomib and epoxomycin) failed to prevent the triptolide-induced RPB1 downregulation, indicating that triptolide acts by stimulating
RPB1 degradation [8]. Being consistent with this notion,
depletion of RBP1 in A549 cells exhibits resistance to the
cytotoxic activity of triptolide.
Together, the available data suggest that triptolide mediates the general transcription inhibition with unique mechanisms distinct from previously characterized transcription
inhibitors (e.g., actinomycin D and a-amanitin) [8].
4. Implication: triptolide overcomes oncogene
addiction
Some tumors show a surprisingly tight dependence on
the continued activity of a specific oncogene, even in the
J. Pan / Cancer Letters 292 (2010) 149–152
presence of additional tumorigenic lesions [30,31]. This
phenomenon is referred to as ‘‘oncogene addiction”. Typical examples include Bcr-Abl in the chronic phase of
chronic myelogenous leukemia (CML), KIT in gastrointestinal stromal tumors (GISTs) and systemic mastocytosis, and
platelet-derived growth factor receptor alpha (PDGFRa) in
hypereosinophilic syndrome (HES) [32–34], Jak2 in myeloproliferative disorders (MPDs). Thus, targeted therapeutics
that specifically inhibit the activity of particular oncoproteins have been developed [35]. Inactivation of tyrosine kinases (e.g., Bcr-Abl, KIT, PDGFRa and Jak2) by selective
small-molecule inhibitors (e.g., imatinib) is effective for
CML, GISTs, and HES [31,36]. Unfortunately, acquired resistance to imatinib develops and is an emerging clinical
problem [37].
Lowering the expression of the oncoproteins Bcr-Abl,
KIT and PDGFRa by transcription inhibitors (e.g., triptolide,
actinomycin D, flavopiridol, roscovitine), Hsp90 inhibitors
(e.g., 17-AAG, IPI-504, celastrol), or translation inhibitors
(e.g., homoharringtonine) can effective kill these oncogene-addicted tumors cells. The loss of total KIT protein
would result in reduced active autophosphorylated KIT,
which leads to subsequent abrogation of downstream signal transduction. Despite the lack of specificity of inhibitors of transcription or translation, addressing oncogene
addiction may provide the biological context for a therapeutic window to selectively kill malignant cells [32,38–
43]. Unlike the use of selective tyrosine kinase inhibitors,
this oncogene-addiction therapeutic approach is not hampered by mutations in the coding sequences of the
oncogenes.
Because triptolide possesses a potent inhibitory effect
of transcription with unique mechanisms, we and others
attempted to investigate its translation efficacy using different oncogene addiction models. First, we discovered
that triptolide potently downregulated Bcr-Abl at the level
of transcription and inhibited the growth and induced
apoptosis in CML cells harboring wild-type Bcr-Abl or
Bcr-Abl-T315I mutation [7]. We confirmed this potent
activity with two pairs of CML cell lines (KBM5 versus
KBM5-T315I, BaF3–Bcr-Abl versus BaF3–Bcr-Abl-T315I)
and primary cells from CML patients with clinical resistance to imatinib [7]. Additionally, triptolide inhibited
the growth of imatinib-resistant Bcr-Abl-T315I as well as
imatinib-sensitive CML cells in nude mouse xenografts;
the protein level of Bcr-Abl in imatinib-sensitive (KBM5)
or -resistant (KBM5-T315I) CML cells was decreased after
triptolide treatment. The antineoplastic activity of triptolide in imatinib-resistant CML cells was confirmed by
Mak et al. who also demonstrated that triptolide-induced
cell death independent of cellular responses to imatinib
in quiescent CD34+ primitive blast crisis CML progenitor
cells [44].
Similarly, we demonstrated that triptolide effectively
inhibits the growth of cells and induces apoptosis in cells
bearing both juxtamembrane and activation loop mutants of KIT, including the imatinib-resistant D816 V
KIT, involved in systemic mastocytosis [25]. In an alternative model, EOL-1 cells bearing FIP1L1-PDGFRa and
BaF3 cells expressing wild-type or T674I FIP1L1-PDGFRa
which showed resistance to imatinib were sensitive to
151
triptolide with downregulated FIP1L1-PDGFRa levels
[24].
The discovery of oncogene addiction in myeloproliferative disorders (MPDs) driven by the gain-of-function mutant Jak2V617F has attracted intense interest in targeted
therapy for MPDs [11]. We examined and found that triptolide potently downregulated the transcription of Jak2
by inhibiting the activity of RNA polymerase. Triptolide
inhibited the in vitro and in vivo growth of tumor cells harboring Jak2V617F [11].
Earlier clinical trials in China revealed that triptolide
achieved a total remission rate of 71% in mononucleocytic
leukemia and 87% in granulocytic leukemia, which was
more effective than any other chemotherapeutic agent currently available [20]. A phase I clinical trial of the effect of a
water-soluble derivative of triptolide on solid tumors is
ongoing in Europe [12]. Further development of triptolide
derivatives may produce promising anticancer drug
candidate.
5. Conflicts of interest
None declared.
Acknowledgements
This study was supported by grants from the National
High Technology Research and Development Program of
China (863 Program Grant 2008AA02Z420 to J. Pan), the
Major Research Plan of the National Natural Science Fund
of China (Grant 90713036 to J. Pan), and the National Basic
Research Program of China (973 Program Grant
2009CB825506 to J. Pan). The author thanks Dr. Sai-Ching
J. Yeung (The University of Texas M.D. Anderson Cancer
Center, Houston, TX, USA) for a critical reading of the
manuscript.
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