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Anticancer activity in human multiple myeloma U266 cells: synergy between cryptotanshinone and arsenic trioxide Pei Liu,a Shi Xu,b Min Zhang,bc Wen Wen Wang,bc Yan Fang Zhang,b Kanwal Rehman,b Hua Naranmandura*b and Zhe Chen*a Arsenic trioxide (As2O3) has been recently established as one of the most effective drugs for the treatment of patients with acute promyelocytic leukemia. However, it has exhibited to be less efficient for the non-promyelocytic leukaemia or other types of malignant tumors. The purpose of the present study was to explore new therapeutic strategies based on As2O3 for human multiple myeloma. Here, we first report cryptotanshinone (CPT) and As2O3 synergy for enhanced cytotoxicity in human multiple myeloma U266 cells. In particular, the apoptosis related proteins (e.g., cleaved poly (ADP-ribose) polymerase (PARP), caspase-3 and -9) were significantly increased by the combination treatment (iAsIII + CPT), whereas, the expression of survival proteins such as Bcl-2 and survivin was suppressed, suggesting that the induction of apoptosis through mitochondrial-mediated apoptotic pathway. In addition, there were no appreciable effects observed in cells after exposure to either As2O3 or CPT alone. In order to better understand the molecular mechanism, we further determined the phosphorylation of STAT3, JNK, ERK and p38. Interestingly, phosphorylation of JNK and p38 were remarkably induced by combination treatment, and no significant inhibition of STAT3 or ERK was
Received 30th December 2012, Accepted 26th February 2013 DOI: 10.1039/c3mt20272k
observed. In addition, induction of apoptosis in human multiple myeloma cells was partially abrogated only by pretreatment with JNK inhibitor and not by p38 inhibitor, suggesting that JNK pathway may play an important role in induction of apoptosis by the combination of iAsIII and CPT. Further studies are needed to evaluate this synergistic anticancer effect in vivo. In the near future, this new approach
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might be used clinically for multiple myeloma (MM) treatment.
Introduction Arsenic trioxide (As2O3) has been successfully used for the treatment of patients with acute promyelocytic leukemia (APL) worldwide, and it is also being developed for the treatment of other forms of tumor and diseases.1,2 Conversely, many reports have indicated that arsenic trioxide as a single-agent has not been as effective as anticipated against non-promyelocytic leukaemia and solid tumors in clinical trials.3–6 Thereby, new therapeutic strategies and/or new adjuvant should be a
Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China. E-mail:
[email protected]; Fax: +86 571-8662-0280; Tel: +86 571-8662-0280 b Department of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. E-mail:
[email protected]; Fax: +86 571-8820-8402; Tel: +86 571-8820-8402 c Chengde Medical College, Chengde 067000, China
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developed to minimize the toxicity and improve the clinical efficacy of arsenic trioxide. Multiple myeloma (MM) is a malignant tumor of plasma cells that causes widespread osteolytic bone damage. It is one of the most common primary tumors of bone and is found in the spine, skull, ribs, sternum and pelvis but may also affect the bone with hematopoietic red marrow.7 Survival rates for MM have traditionally been low, but new therapies and drugs (e.g., high-dose chemotherapy, bone marrow transplantation and aggressive supportive) have improved the survival rates remarkably.8 Despite these advances, MM has been known to eventually relapse in the majority of the patients, secondary to drug resistance. Thus, newer treatments with good safety profiles are needed to improve the quality of responses and to extend overall survival.7,9 The efficacy of As2O3 in MM has been evaluated in several studies.7,10,11 Munshi et al. (2001) has reported that As2O3 can inhibit proliferation and induce apoptosis in MM cells in vitro,
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Scheme 1
Metallomics
Chemical structure of arsenic trioxide and cryptotanshinone.
suggesting As2O3 would be a good drug as an emerging therapy for multiple myeloma. In addition, Hayashi et al., has indicated that As2O3 at clinically achievable levels (e.g., 2–5 mM) could induce apoptosis in drug-resistant MM cell lines or primary patient cells.12,13 However, it has been indicated that MM cells lines as well as primary cells derived from patient exhibited resistance to As2O3.14,15 Cryptotanshinone (CPT), a diterpene quinone isolated from the root of Salvia miltiorrhiza, is known for its anti-inflammatory, anti-cancer, antioxidative and anti-angiogenic activities.16,17 Recent studies have shown that cryptotanshinone exerts potential anticancer activity through targeting STAT3 signaling, inhibiting the signaling pathway of the mammalian target of rapamycin (mTOR) and mTOR-mediated cyclin D1 expression and Rb phosphorylation. Likewise, it has been found that CPT could also suppress VEGFR-3 mediated ERK1/2 phosphorylation and small GTPase pathways in number of human cancer cell lines.18 Moreover, CPT has also been proved to sensitize several cancer cells to anti-cancer agents, including TNF-a and Fas.17 Our previous studies demonstrated that cryptotanshinone could induce cell cycle arrest and apoptosis through suppressing the protein levels of cylcin D1 and Bcl-2 in doxorubicin-resistant chronic myelogenous leukemia cells, supporting the development of cryptotanshinone as an apoptosis inducer or chemosensitizer in combined therapy.19 To develop a novel therapeutic strategy for MM, we have examined the anti-cancer effect of As2O3 and cryptotanshinone (chemical structures are illustrated in Scheme 1) alone and as combination treatment on human multiple myeloma U266 cell line. Here, we found that U266 cells were relatively resistant after exposure to either As2O3 or CPT alone. Surprisingly, combination of As2O3 (1 mM) with CPT (15 mM) at sub-toxic concentrations significantly reduced the cells survival. Moreover, combination treatment exerted synergistic effects on the induction of apoptosis in U266 cells via activation of JNK pathway. These findings suggested that combination of As2O3 with CPT may be useful for the treatment of human multiple myeloma.
Experimental Reagents Penicillin, streptomycin, RPMI 1640, protease inhibitor tablets and fetal bovine serum (FBS) were purchased from Invitrogen. Arsenic trioxide was purchased from Sigma (St. Louis, MO, USA)
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and dissolved in 0.1 M sodium hydroxide solution to make a trivalent arsenite (iAsIII) stock solution for use. Cryptotanshinone was purchased from Must Bio-Technology Co., LTD (Chengdu, China) and dissolved in 10 mmol L 1 DMSO as stock solution. All stock solutions were stored in the dark at 4 1C. The antibodies for detecting pro-caspase 3, cleaved-caspase 3, pro-caspase 9, cleaved-caspase 9, PARP, Bcl-2, survivin, XIAP, Bax, Bak, cytochrome c, ERK1/2, phospho-ERK1/2, JNK, phospho-JNK, p38, phospho-p38, STAT3, p-STAT3Tyr705, p-STAT3Ser727 and b-actin were purchased from Cell Signaling Technology. Cell culture Human multiple myeloma U266 cells were seeded at a density of 1.0 106 in T25 flask, and were maintained in logarithmic growth phase RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) (Invitrogen, Grand Island, USA), 100 U mL 1 penicillin, and 100 mg mL 1 streptomycin, at 37 1C in 5% CO2 atmosphere. Twenty-four hours after seeding, cultures were washed twice with PBS, fresh medium was added, and then the cells were treated with iAsIII, CPT alone or combination of two compounds for 24 h. MTT assay for cellular viability U266 cells were seeded at a density of 2 104 cells per 100 mL per well in 96-well microtiter plates (Promega Corporation). Twenty-four hours post-seeding, the cultures were washed twice with PBS and then exposed to various concentrations of iAsIII, CPT and combination of iAsIII and CPT for 24 h. Then, 20 mL of an MTT solution was added to each well, and the plates were incubated for an additional 3 h at 37 1C. Cell viability was measured as the absorbance at 490 nm with a microplate reader and expressed as a percentage of the control level. Assessment of apoptosis Apoptosis was measured by flow cytometry analysis of phosphatidylserine externalization. Briefly, arsenic-treated cells were counted, resuspended in binding buffer (Facscalibur, BD Biosciences, San Jose, CA), and stained with 5 mg mL 1 FITCconjugated annexin V and propidium iodide (PI) for 15 min in the dark at room temperature, according to the manufacturer’s instructions (BD Biosciences, San Jose, CA). Cells were screened by flow cytometry (Facscalibur, BD Biosciences, San Jose, CA). The FL-1 and FL-2 channels were used simultaneously to gate annexin V-positive cells and PI-positive cells, respectively. Isolation of mitochondria from cells Mitochondria isolation was performed as described previously.20 In brief, U266 cells were washed twice with PBS, and then minced in ice-cold homogenization buffer A (230 mM mannitol, 70 mM sucrose, 10 mM Tris-HCl, 1 mM EDTA2Na and 0.5% bovine serum albumin (BSA), pH 7.4) by using a Dounce homogenizer to make 30% (w/v) homogenates, and then keep the on ice for 5 min to remove unbroken cells and cell debris. After removing the unbroken cells, the supernatant was centrifuged twice at 700g for 10 min at 4 1C to obtain the cellular nuclear fraction and supernatant fraction. Mitochondria were
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isolated by subjecting the supernatant to centrifugation at 12 000g for 10 min at 4 1C to obtain pellet. The pellet was washed twice and re-suspended in the isolation buffer B (230 mM mannitol, 70 mM sucrose, 10 mM Tris-HCl, 1 mM EDTA2Na) for use.
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Western blot analysis U266 cells were washed once in PBS supplemented with complete protease inhibitor (Roche, Mannheim, Germany). Washed cell pellets (3 106 cells) were resuspended in protease buffer containing 10 mM Tris-buffer (pH 7.6), 1.5 mM MgCl2, 1 mM EDTA, 10 mM KCl, 1 mM phenylmethylsulphonyl fluoride (PMSF) and protease inhibitor tablets (contains 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), E-64, bestatin, leupeptin, aprotinin, and EDTA for inhibition of serine, cysteine, and metalloproteases). Whole cell extracts were prepared according to the published methods.20 Briefly, U266 cells were washed once in cold PBS, followed by the cell pellets were lysed by a single freeze-thaw cycle in the presence of protease inhibitors and whole cell extracts were obtained by centrifugation at 14 000 g for 40 min after extraction with 0.5 M NaCl. Protein concentrations were determined using the Bio-Rad microprotein assay using bovine serum albumin as the standard. Twenty-five microgram of each protein sample was resolved by 10 or 12% SDS-PAGE and electroblotted onto nitrocellulose membranes (Bio-Rad, Mississauga, ON). The membranes were blocked for 1 h at room temperature in PBS containing 5% skim milk plus 0.1% Tween-20 (PBST) and incubated overnight at 4 1C with different first antibodies, followed by incubation with a horseradish-peroxidase-conjugated secondary antibody (Jackson ImmunoResearch, West Grove, PA; 1 : 10 000 dilution) for 1 h at room temperature. Statistical analysis Each viability value represents the mean S.D. from four determinations, and IC50 values were calculated from the loglog plot between the percentage of viable cells. Subsequently, each experiment was performed at least three times. Statistical analysis of data was carried out using a one-way ANOVA followed by Holm–Sidak pairwise multiple comparison test (SigmaPlot, Systat Software Inc.), and a probability value of less than 0.05 (*p o 0.05) was accepted as a significant difference.
Results As2O3 is absolutely in the hydrolyzed form, namely, arsenite (iAsIII) at physiological condition or pH 7.4. Thereby, iAsIII represents As2O3 in the current study. Fig. 1A–C shows the cell viability of U266 cells after exposure to iAsIII, CPT alone or combination of iAsIII and CPT for 24 h. Interestingly, the viability of U266 cells was not significantly affected by exposure to either iAsIII or CPT alone at 1 or 15 mM (Fig. 1A and B), whereas were found to be much more sensitive to the combination treatment of iAsIII and CPT at sub-toxic concentrations of 1 mM and 15 mM respectively and the cells viability was reduced to approximately 50% of control. In fact,
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Fig. 1 Effect of arsenic, cryptotanshinone (CPT) or combination of iAsIII and CPT on the viability of human multiple myeloma U266 cells. Briefly, U266 cells were seeded at a density of 2 104 cells per well in triplicate in 96-well plates. The cells were exposed to indicate concentrations of iAsIII (A), cryptotanshinone (B) or combination of 1 mM iAsIII and 15 mM CPT (C) for 24 h. Cell viability was determined by MTT assay as described. Data are expressed as mean values S.D.
cells were still surviving more than 85% after exposure to either iAsIII or CPT at the 1 or 15 mM, and thereby these concentrations were used in subsequent experiments (Fig. 1). In order to understand the mechanism of synergistic effects of iAsIII with CPT on induction of U266 cell death, apoptosis related proteins such as Bcl-2, survivin, XIAP, Bax, and Bak were also evaluated after exposure to iAsIII, CPT alone or to the combination of iAsIII and CPT. As anticipated, anti-apoptotic proteins Bcl-2, survivin and XIAP were significantly decreased after exposure to combination of iAsIII and CPT. In addition, pro-apoptosis related proteins Bax and Bak were also decreased sharply in cytosolic fraction, whereas Bax was significantly
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Fig. 3 Cleavage of caspase-3, -9 and PARP induced in U266 cells by combination of iAsIII and CPT. U266 cells were exposed to 1 mM iAsIII and 15 mM CPT alone or combination of the two compounds for 24 h. Cleaved caspase-3, -9 and poly (ADP-ribose) polymerase (PARP) were determined by immunoblotting using specific antibodies. Beta-actin was used as a loading control.
Fig. 2 Combination of iAsIII and CPT induces mitochondrial signaling apoptotic pathway in human multiple myeloma U266 cells. U266 cells were exposed to 1 mM iAsIII and 15 mM CPT alone or combination of the two compounds for 24 h. Proteins were extracted from mitochondria and cytoplasmic fractions of U266 cells. Anti-apoptotic proteins Bcl-2, survivin and XIAP (A), pro-apoptotic proteins Bak and Bax in cytoplasm (B), Bax in mitochondria (C) and release of cytochrome c from mitochondria to cytoplasm (D) were determined by immunoblotting, as described in Experiment. Beta-actin and COX IV were used as loading controls.
increased in mitochondrial fraction following combination treatment (Fig. 2C), suggesting that the combination treatment may possibly enhance the induction of apoptosis in U266 cells (Fig. 2). More interestingly, anti-apoptotic proteins Bcl-2 and survivin were increased by exposure to iAsIII alone at 1 mM, indicating that MM cells resistance to arsenic might probably be due to Bcl-2 up regulation. Likewise, no appreciable cytochrome c was released from the mitochondria by exposure to 1 mM of iAsIII or 15 mM of CPT alone, while it was significantly
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increased in cytoplasm by combination treatment, as shown in Fig. 2D. On the other hand, as the caspase cascade can be activated by few different routes,21 in the present study, we have also determined the activation of caspase family such as 3 and 9 in cells, as shown in Fig. 3. Effect of combination treatment on induction of activated caspases was observed to be much stronger than that of single treatment with iAsIII or CPT, and the cleaved caspase 3 and 9 were clearly observed. In addition, the cleaved PARP was also significantly increased by the combination treatment, suggesting that the combination of AsIII and CPT could increase the induction of apoptosis in U266 cells. It has been documented that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is inhibited by exposure to CPT.16 Thereby, we hypothesized that the inhibition of STAT3 activity may contribute in inducing apoptosis. Fig. 4 shows the changes in phosphorylation of STAT3 and inactivated STAT3 after exposure to different compounds. Arsenic alone or combination treatment did not affect the STAT3 phosphorylation on Tyr705 and Ser727, however, CPT reduced
Fig. 4 Determination of STAT3 in U266 cells by exposure to combination of iAsIII and CPT. U266 cells were exposed to 1 mM iAsIII and 15 mM CPT alone or combination of the two compounds for 4 h. STAT3 and phosphorylation of Tyr705 and Ser727 on STAT3 were determined by immunoblotting using specific antibodies.
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the STAT3 phosphorylation on Tyr705 as compared with that of control, implying that the STAT3 signaling pathway may not have been significantly involved in the induction of apoptosis. The MAPK pathways play essential roles in the regulation of cellular response, including cell apoptosis, survival, proliferation and differentiation, thereby, the activation of extracellular signal regulated kinases (ERKs), JNK, and p38 were assessed, as shown in Fig. 5. U266 cells were treated with As2O3, CPT alone or with the combination of As2O3 with CPT for 4 h, and the cell lysates were then immunoblotted with pan-/phospho-specific antibodies. Interestingly, phosphorylated JNK and p38 were not activated significantly by exposure to iAsIII or CPT alone, while it was remarkably activated by the combination treatment, suggesting that up regulation of JNK or p38 may be involved in the cell death (Fig. 5A).
In order to better understand the molecular mechanism, we used the JNK and p38 inhibitors to determine the changes in apoptosis. When cells were pretreated with p38 inhibitor (SB203580), no significant reduction of cleaved caspase-3 and -9 was observed by the combination treatment (Fig. 5B), whereas a significant reduction of cleaved caspase-3 and -9 was observed by pre-treatment with JNK inhibitor (SP600125), suggesting that the induction of apoptosis occurred at least in part, via JNK activation. To further confirm our hypothesis, induction of apoptosis was also examined in the presence of p38 and JNK inhibitors by flow cytometry, as shown in Fig. 6. Inhibition of p38 did not prevent the induction of apoptosis after exposure to combination of iAsIII with CPT, while apoptosis was significantly reduced in the presence of JNK inhibitor after exposure to combination treatment. These results were found to be consistent with the changes in apoptosis related proteins (Fig. 5B).
Discussion
Fig. 5 Activations of JNK and P38 in U266 cells by exposure to combination of iAsIII and CPT. U266 cells were treated with 1 mM iAsIII, 15 mM CPT alone or combination of iAsIII (1 mM) with CPT (15 mM) for 4 h, the total level of JNK, P38 and ERK1/2 or phosphorylated JNK, P38 and ERK1/2 were determined by immunoblotting using specific antibodies (A). Cells were pretreated with 20 mM JNK inhibitor SP600125 for 3 h and then exposed to the combination of iAsIII and CPT for 4 h. Total levels of JNK and ERK1/2 or phosphorylated JNK and ERK1/2 were determined (B) as described above.
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Inorganic arsenic is known to be a human carcinogen, and its toxicity is considered to be dependent on the chemical values, especially the trivalent arsenic are much more toxic than that of corresponding pentavalent ones.22–24 As2O3 (i.e., trivalent species), a therapeutic agent used for thousands of years in traditional medicine, has proven to be an effective drug for the treatment of acute promyelocytic leukemia (APL).1,2 Long-term As2O3 therapy is able to induce a prolonged molecular remission in APL patients.2 Recently, it has also been used against some other solid tumors or non-promyelocytic leukaemia in clinical trials.5,6 Multiple myeloma (MM), known as plasma cell myeloma, is the second-most common cancer of the blood.12,25,26 However, it has been reported that As2O3 therapy as a single-agent has limited efficacy against MM as compared to APL.27,28 Although high concentration of As2O3 may increase overall survival rate in MM patients, however most of the patients may not tolerate such high-dose chemotherapy.7 In addition, high-dose As2O3 can also cause a number of side effects such as cytopenia, deep vein thromboses, infectious complications.27–29 Therefore, As2O3 should be combined with other standard or low toxic anticancer agents to minimize the side effects and enhance the anticancer activity. To develop new therapeutic approaches that can increase anticancer activity and reduce toxicity of arsenic, in the current study, cryptotanshinone (CTP) was selected as combination treatment agent with iAsIII to determine the synergistic effects on human multiple myeloma U266 cells. Here, for the first time we have reported that cryptotanshinone is able to increase the cytotoxicity of iAsIII on human multiple myeloma U266 cells. MTT assay has shown that cell viability was not significantly affected by exposure to 1 mM of iAsIII or 15 mM of CPT alone, while the combination of iAIII and CPT had strong effect on reducing the cell viability (Fig. 1C). A similar result was also observed in other multiple myeloma RPMI 8266 cell line after combination treatment of iAsIII with CPT (Data not shown).
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Fig. 6 Inhibition of JNK activation partially blocked the induction of apoptosis in U266 cells after exposure to the combination of iAsIII and CPT. U266 cells were pretreated with 20 mM JNK inhibitor SP600125 or P38 inhibitor SB203580 for 3 h and then exposed to iAsIII (1 mM) and CPT (15 mM) alone or combination the two compounds for 24 h. Cell apoptosis was detected using annexin V-FITC (FL1 channel) and PI-Staining (FL2 channel) by flow cytometry.
These results suggested that the CTP may probably increase the efficacy of iAsIII in human MM cells. In other words, we predict iAsIII may also be able to increase the efficacy of CPT, but this is not discussed in the present study. Activation of mitochondrial-mediated apoptotic pathways is one of the most well characterized mechanisms of action of iAsIII. We have clearly revealed the mechanism underlying the combination of iAsIII and CPT on induction of apoptosis in U266 cells. Anti-apoptotic proteins such as Bcl-2, survivin and XIAP were sharply decreased in U266 cells after combination treatment (Fig. 2A). Likewise, the pro-apoptotic proteins Bax were also significantly decreased in cytoplasm (Fig. 2B) and increased in mitochondria (Fig. 2C), suggesting these proapoptotic proteins in cytoplasm moved towards mitochondria and facilitated the release of Cyt c from mitochondria (Fig. 2D) as well as activated caspase-3, -9 and PARP to induce apoptosis (Fig. 3). More interestingly, U266 cells exposed to iAsIII alone resulted in up-regulation of anti-apoptotic proteins Bcl-2 and survivin, implying that these proteins may contribute for the resistance of iAsIII in human MM cells. On the other hand, STAT3 is considered to be a target of CPT,16 however there was no significant differences observed in U266 cells after combination treatment of iAsIII and CPT (Fig. 4). Cells growth or apoptosis process is known to be controlled by a diverse range of cell signals. In the current study, we found that the pro-apoptotic and anti-survival activities can be regulated by c-Jun NH2-terminal kinases (JNK) and p38 signaling pathways by the combination of iAsIII and CPT. Phosphorylation of JNK and p38 were remarkably induced by the combination exposure, and no appreciable changes were observed in STAT3 and ERK1/2 (Fig. 4 and 5A), suggesting the induction of apoptosis was probably related at least in part to these two signaling pathways. In order to better understand the molecular mechanism, we further determined the induction of
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apoptosis by inhibiting the p38 and JNK after combination treatment. Induction of apoptosis was only significantly attenuated by inhibition of JNK but not by the p38 inhibition (Fig. 5B and 6), suggesting the induction of apoptosis by combination treatment is, at least in part, through JNK pathway.
Conclusions We provided new evidence that As2O3 at low concentration is able to increase the induction of apoptosis in combination with CPT, and this combination treatment may be a good therapeutic approach for the treatment of human multiple myeloma.
Disclosure The authors report no conflicts of interest.
Abbreviations APL As2O3 iAsIII CPT
acute promyelocytic leukemia arsenic trioxide arsenate cryptotanshinone
Acknowledgements The authors wish to acknowledge the National Natural Science Foundation of China (No. 81001477, 81274138), Zhejiang Provincial Natural Science Foundation of China (No. R2110231, Y12H29003), the Key Science and Technology Innovation Team of Zhejiang Province (2010R50047) and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents. Foundation of Traditional Chinese Medical Sciences, Zhejiang Province (2010ZA048) and Science and Technology
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Department of Zhejiang Province Public Technology Research Program (2011C37014). 11
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