Search tips
Search criteria 


Logo of mmrLink to Publisher's site
Mol Med Rep. 2017 January; 15(1): 103–110.
Published online 2016 November 28. doi:  10.3892/mmr.2016.5969
PMCID: PMC5355719

Anti-proliferative activity of epigallocatechin-3-gallate and silibinin on soft tissue sarcoma cells


Disseminated soft tissue sarcomas (STS) present a therapeutic dilemma. The first-line cytostatic doxorubicin demonstrates a response rate of 30% and is not suitable for elderly patients with underlying cardiac disease, due to its cardiotoxicity. Well-tolerated alternative treatment options, particularly in palliative situations, are rare. Therefore, the present study assessed the anti-proliferative effects of the natural compounds epigallocatechin-3-gallate (EGCG), silibinin and noscapine on STS cells. A total of eight different human STS cell lines were used in the study: Fibrosarcoma (HT1080), liposarcoma (SW872, T778 and MLS-402), synovial sarcoma (SW982, SYO1 and 1273) and pleomorphic sarcoma (U2197). Cell proliferation and viability were analysed by 5-bromo-2′-deoxyuridine and MTT assays and real-time cell analysis (RTCA). RTCA indicated that noscapine did not exhibit any inhibitory effects. By contrast, EGCG decreased proliferation and viability of all cell lines except for the 1273 synovial sarcoma cell line. Silibinin exhibited anti-proliferative effects on all synovial sarcoma, liposarcoma and fibrosarcoma cell lines. Liposarcoma cell lines responded particularly well to EGCG while synovial sarcoma cell lines were more sensitive to silibinin. In conclusion, the green tea polyphenol EGCG and the natural flavonoid silibinin from milk thistle suppressed the proliferation and viability of liposarcoma, synovial sarcoma and fibrosarcoma cells. These compounds are therefore potential candidates as mild therapeutic options for patients that are not suitable for doxorubicin-based chemotherapy and require palliative treatment. The findings from the present study provide evidence to support in vivo trials assessing the effect of these natural compounds on solid sarcomas.

Keywords: soft tissue sarcoma, synovial sarcoma, liposarcoma, fibrosarcoma, epigallocatechin, silibinin


Soft tissue sarcomas (STS) are a heterogeneous group of solid tumours arising from transformed cells of mesenchymal origin. They may occur throughout the body and represent ~1% of all adult malignancies (1). In patients with primary diagnosed STS without distant metastasis, standard treatment involves surgical resection with negative margins, typically followed by adjuvant radiation to decrease the risk of recurrence (2,3). However, almost half of all patients with STS develop distant metastases, rendering them unsuitable for surgery (4,5). If metastasis has occurred, the median survival time regardless of chemotherapeutic treatment is <12 months (6,7). A limited number of chemotherapeutic agents, including doxorubicin and ifosfamide, are effective for the treatment of metastatic STS (2). However, the response rates of these agents are poor and often do not result in significant extension of survival (8). Doxorubicin is the predominant chemotherapeutic agent used for the treatment of metastatic STS, and has a response rate of ~30% (9,10). The combination of doxorubicin and ifosfamide exhibits greater response rates compared with doxorubicin alone; however, it is associated with severe short- and long-term adverse effects, including bone marrow suppression and cardiomyopathy (1113).

A multicentre analysis by the European Organisation for Research and Treatment of Cancer (trial 62012) on 455 patients with advanced STS indicated that an intensified combination treatment with doxorubicin and ifosfamide is not suitable for treatment of locally advanced or metastatic STS as a result of the serious adverse effects, and should therefore only be used with a view to tumour shrinkage (13). Furthermore, the versatility of doxorubicin is limited by dose-associated and cumulative myocardial toxicity, particularly in older patients with a history of cardiac disease (14). However, the incidence of STS increases markedly >50 years of age, when the prevalence of cardiac diseases is also greater (15). Currently, there are no efficacious and safe agents for the palliative treatment of patients who may not undergo doxorubicin-based chemotherapy due to underlying cardiac disease. Therefore, the development of novel therapeutic agents is required for the treatment of STS.

A review of the literature reveals various potential well-tolerated and natural phytochemicals that exhibit anti-neoplastic effects on malignant cells, including the compounds epigallocatechin-3-gallate (EGCG), silibinin and noscapine. EGCG is the most abundant catechin in green tea and demonstrates anti-inflammatory, antioxidant and antineoplastic activities (1618). Various in vitro studies have revealed that EGCG exhibits anticancer activity in lung (19), prostate (20), colon (21), gastric (22), breast (23) and cervical carcinoma cells (24). To date, EGCG has undergone various phase II trials and has been demonstrated to be well-tolerated following oral administration (2529). The most frequent adverse reactions observed were gastrointestinal reactions, including nausea and vomiting. In rare cases, patients presented with elevated serum alanine aminotransferase levels following the administration of high doses of oral EGCG; however, liver function tests returned to baseline following discontinuation of ECGC (30). Therefore, EGCG is considered to be a safe and well-tolerated agent for the treatment of cancer patients (31,32).

Silibinin is the primary active constituent of silymarin, a standardized extract from the seeds of the milk thistle plant (Silybum marianum). Silibinin is available as a therapeutic agent in various European countries and is used for the treatment of toxic liver damage, particularly due to Amanita phalloides intoxication (33). It is well tolerated in cancer patients (34,35) and has demonstrated anti-neoplastic effects in various malignant cell lines including HT1080 fibrosarcoma cells (3640).

Noscapine is a naturally occurring opium alkaloid and a widely used antitussive drug that is non-addictive and has a low toxicity profile (41). As a tubulin-binding agent, various preclinical studies have established its tumour-inhibitory effects in a wide range of malignancies (4245). Currently, noscapine is undergoing phase II clinical trials for cancer chemotherapy (46).

Based on these results, the present study aimed to investigate the anti-proliferative activity of EGCG, silibinin and noscapine on eight different STS cell lines, including fibrosarcoma, liposarcoma, synovial sarcoma and pleomorphic sarcoma cells.

Materials and methods

Cell lines

Eight different human STS cell lines were used in the present study: HT1080 (fibrosarcoma), SW872 (liposarcoma), T778 (liposarcoma), MLS-402 (liposarcoma), SW982 (synovial sarcoma), SYO1 (synovial sarcoma), 1273 (synovial sarcoma) and U2197 (pleomorphic sarcoma/malignant fibrous histiocytoma). HT1080, SW872 and SW982 were purchased from CLS Cell Lines Service GmbH (Eppelheim, Germany) and were cultured in Dulbecco's modified Eagle's medium (DMEM; PAN-Biotech GmbH, Aidenbach, Germany) supplemented with 10% foetal bovine serum (FBS; Thermo Fisher Scientific, Inc., Waltham, MA, USA), 1% penicillin (100 U/ml) and 1% streptomycin (100 µg/ml; PAN-Biotech GmbH). The well-differentiated T778 liposarcoma cell line and the MLS-402 myxoid liposarcoma cell line were donated by Professor Pierre Åman (University of Gothenburg, Gothenburg, Sweden) and Professor Ola Myklebost (Oslo University Hospital, Oslo, Norway), respectively. T778 and MLS-402 cells were cultured in RPMI (PAN-Biotech GmbH) supplemented with 10% FBS and 1% penicillin/streptomycin as previously described (47,48). The SYO-1 and 1273 cell lines were donated by Dr Akira Kawai (National Cancer Center, Tokyo, Japan) and Professor Olle Larsson (Karolinska Institutet, Stockholm, Sweden) (49,50). The SYO-1 cells were cultured in DMEM supplemented with 10% FBS, 1% penicillin/streptomycin and 0.5% sodium pyruvate. The 1273 cells were cultivated in Ham's F12 (PAN-Biotech GmbH) supplemented with 10% FBS and 1% penicillin/streptomycin. The U2197 cell line was obtained from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and was cultured in minimum essential medium (PAN-Biotech GmbH) supplemented with 20% FBS, 0.165% sodium bicarbonate and 1% penicillin/streptomycin (51). All cultures were maintained at 37°C in a humidified 5% CO2 atmosphere.

Phytotherapeutic agents

EGCG, silibinin and noscapine were obtained from Sigma-Aldrich; Merck Millipore (Darmstadt, Germany). The stock solution was dissolved in dimethyl sulfoxide (DMSO; Carl Roth GmbH & Co. KG, Karlsruhe, Germany) and further diluted in DMEM to concentrations of 50 µM (EGCG), 150 µM (silibinin) and 30 µM (noscapine) for all assays. These concentrations have been demonstrated to inhibit proliferation and induce apoptosis in various malignant cell lines (36,52,53).

Cell viability assay

Metabolic activity was measured using an MTT assay. Cells were seeded in 96-well plates (Corning Incorporated, Corning, NY, USA) at 1×104 cells per well. The following day, the three agents were added in the aforementioned concentrations for 24 h. Subsequently, 50 µl 0.5 mg/ml MTT (Sigma-Aldrich; Merck Millipore) was added for 4 h. MTT is a yellow dye that is reduced to purple formazan in the mitochondria of vital cells. Cells were lysed following the addition of 200 µl DMSO and 25 µl glycine buffer (containing 0.1 M glycine and 0.1 M NaCl, adjusted to pH 10.5 with NaOH) per well. The quantity of integrated dye represented the level of metabolism and was measured at a wavelength of 562 nm using an Elx808 Ultra Microplate Reader (BioTek Instruments GmbH, Bad Friedrichshall, Germany).

Proliferation assay

To quantify the effects of EGCG, silibinin and noscapine on cell proliferation, a colorimetric cell proliferation 5-bromo-2′-deoxyuridine (BrdU)-ELISA assay (Roche Diagnostics GmbH, Mannheim, Germany) was performed according to the manufacturer's protocol. Briefly, cells were seeded at 1×104 cells/well in 96-well plates and cultured for 24 h. The phytotherapeutic agents were subsequently added in the appropriate concentrations for 24 h. The BrdU labelling solution was added and incubated for a further 24 h. BrdU, a pyrimidine analogue, integrates into the DNA of proliferating cells. The level of proliferation was quantified by the light emission detected via an Orion Microplate Luminometer (Berthold Detection Systems GmbH, Pforzheim, Germany). Cell proliferation was determined in quadruplicate. The results are expressed as a percentage of the proliferation of DMSO-treated control cells.

Real-time cell analysis (RTCA)

Cells were seeded in two 8-well plates with an integrated microelectronic sensor array in 600 µl culture medium (iCELLigence Real Time Cell Analyser; ACEA Biosciences, San Diego, CA, USA). After 24 h, the therapeutic agents were added for a total volume of 50 µl. The cell proliferation and survival were monitored in real-time by measuring the cell-to-electrode responses of the seeded cells. In each individual E-well, the cell impedance was measured and converted to cell index (CI) values by the RTCA software version 1.2 (Roche Diagnostics GmbH) (54). The graphs were generated in real-time by the iCELLigence system. Untreated and DMSO-treated cells served as controls.

Statistical analysis

Data analyses were performed using the statistical program SPSS 16 (SPSS, Inc., Chicago, IL, USA). Data are expressed as the mean ± standard deviation. Comparisons between the experimental groups in BrdU and MTT assays were performed using one-way analysis of variance followed by post-hoc Tukey's test. P<0.05 was considered to indicate a statistically significant difference.


EGCG significantly inhibits the proliferation and viability of STS cell lines

As indicated by the BrdU assay, the proliferation of all eight human STS cell lines was inhibited by EGCG (Fig. 1). By MTT analysis, EGCG decreased the viability of seven cell lines (Fig. 2). To evaluate the proliferation and viability of cells continuously over a longer time period, RTCA was performed. The viability, adhesion and proliferation of the cells were monitored prior to and during EGCG treatment in real time for 160 h (Figs. 35). EGCG markedly decreased the CI of all STS cell lines except the 1273 synovial sarcoma cell line. The administration of EGCG reduced the CI of the HT1080 fibrosarcoma cell line and the U2197 pleomorphic sarcoma cell line (Fig. 3). All three liposarcoma cell lines (SW872, T778 and MLS-402) exhibited a continuously decreased CI during EGCG treatment compared with untreated or DMSO-treated cells (Fig. 4), as did the remaining two synovial sarcoma cells lines (SW982 and SYO1; Fig. 5).

Figure 1.
Effects of silibinin, ECGC and noscapine on cell proliferation. The proliferative activity of all cell lines was measured by BrdU assay. The assay was performed following 24 h of treatment with DMSO, silibinin, ECGC or noscapine. For clarity, the BrdU-labelling ...
Figure 2.
Effects of silibinin, ECGC and noscapine on cell viability. The cell viability of all cell lines was measured by MTT assay. The assay was performed following 24 h of treatment with DMSO, silibinin, ECGC or noscapine. For clarity, the MTT-index of the ...
Figure 3.
Real-time cell analysis of fibrosarcoma and malignant fibrous histiocytoma cells. (A) HT1080 fibrosarcoma cells and (B) U2197 pleomorphic sarcoma/malignant fibrous histiocytoma cells were seeded in 8-well plates with an integrated microelectronic sensor ...
Figure 4.
Real-time cell analysis of liposarcoma cell lines. (A) SW872, (B) T778 and (C) MLS-402 liposarcoma cells were seeded in 8-well plates with an integrated microelectronic sensor array. The CI reflecting the number of viable cells was monitored continuously ...
Figure 5.
Real-time cell analysis of synovial sarcoma cell lines. (A) SW982, (B) SYO1 and (C) 1273 synovial sarcoma cells were seeded in 8-well plates with an integrated microelectronic sensor array. The CI reflecting the number of viable cells was monitored continuously ...

Silibinin significantly decreases the proliferative activity and viability of STS cell lines

Treatment with silibinin significantly reduced the proliferation of seven STS cell lines (Fig. 1), and significantly decreased the cell viability of all eight assessed STS cell lines, as analysed by MTT assay (Fig. 2). By RTCA, silibinin was the only compound that exhibited a strong inhibitory effect on all three synovial sarcoma cells (Fig. 5). In addition, silibinin reduced the CI of all liposarcoma cell lines; however, not to the extent of EGCG. Only the U2197 pleomorphic sarcoma cell line did not respond to silibinin treatment.

By RTCA, STS cell lines are unaffected by noscapine treatment

Noscapine exhibited cytostatic effects on STS cells, as assessed using BrdU (Fig. 1) and MTT (Fig. 2) assays at 24 h. However, these effects could not be validated by RTCA over a longer time period. The proliferation inhibition resulting from noscapine treatment in six cell lines at 24 h did not result in a continual decrease of the CI. In all cell lines, the CI of noscapine-treated cells increased steadily and was comparable to the CI of DMSO-treated or untreated control cells during the 160 h of real-time analysis (Figs. 35).


STS are a heterogeneous group of rare mesenchymal malignancies. To date, systemic treatment options are limited following metastasis. Patients with distant metastases have a median survival time of less than one year despite systemic chemotherapy (6,7). Due to the infrequent and heterogeneous nature of STS the development of novel systemic therapeutic agents is challenging and novel chemotherapy strategies are lacking. Therefore, the development of well-tolerated and effective chemotherapeutic agents for the treatment of STS is required.

The present study assessed the cytostatic effects of the naturally occurring compounds noscapine, silibinin and EGCG on eight STS cell lines. By RTCA, noscapine did not exhibit any relevant anti-proliferative effects (Table I). In contrast, silibinin and EGCG exerted cytostatic effects in almost all examined STS cell lines, as assessed by BrdU, MTT and RTCA. Administration of EGCG decreased proliferation and viability of all liposarcoma cell lines and two synovial sarcoma cell lines for more than five days. In addition, it inhibited HT1080 fibrosarcoma and U2197 pleomorphic sarcoma cells. Of the three analysed compounds, EGCG exerted the greatest anti-proliferative activity in the three assessed liposarcoma cell lines, rendering it a potential agent of interest. Liposarcomas represent the most frequent somatic STS subtype and respond poorly to anthracycline-based chemotherapy, with well-differentiated and de-differentiated tumours exhibiting response rates of only 12 and 13%, respectively (55). Pleomorphic liposarcomas are the least responsive to chemotherapy, with a response rate of 5%, whereas myxoid liposarcomas have been revealed to be the most sensitive to chemotherapy, exhibiting response rates of 44–48% (5658). In the present study, EGCG exhibited a distinct inhibitory effect on T778 cells from a well-differentiated liposarcoma, SW872 cells from a pleomorphic liposarcoma and MLS-402 cells from a myxoid liposarcoma. Although these findings were in vitro, they suggested a potential anti-proliferative activity of EGCG on liposarcoma cells that should be further investigated in vivo.

Table I.
Summary of the cytostatic effects of EGCG, silibinin and noscapine, as assessed by MTT and BrdU assays and RTCA.

In comparison with EGCG, the inhibitory effect of silibinin was reduced in liposarcoma cells, but greater in synovial sarcoma cells. Silibinin significantly decreased proliferation and viability in all three synovial sarcoma cell lines. Although synovial sarcomas have typically been considered relatively chemosensitive, the European Organisation for Research and Treatment of Cancer recently reported a chemotherapy response rate of only 28% for patients with advanced synovial sarcoma (59). Therefore, there remains a requirement for alternative cytostatic agents for the treatment for synovial sarcomas, and the in vitro effects of silibinin demonstrated in the present study should be further examined in vivo.

A literature review revealed that the green tea polyphenol EGCG has further notable properties. Various in vivo studies have confirmed that EGCG mitigates doxorubicin-induced cardiotoxicity by suppressing oxidative stress (6063). The oxygen free radical scavenging ability of EGCG has been demonstrated to protect cardiomyocytes from doxorubicin-mediated cardiotoxicity according to histopathological analysis (64). Furthermore, EGCG has been revealed to synergistically enhance the anticancer activity of doxorubicin in various in vivo studies on prostate and liver cancer (6567). Notably, similar chemosensitizing and chemopreventive activities have been described for silibinin; in vivo studies revealed that silibinin synergistically enhances the apoptosis-inducing activity of doxorubicin and ameliorates doxorubicin-induced cardiotoxicity (6873). Therefore, EGCG and silibinin may additionally function as chemopreventives and chemosensitizers for doxorubicin, which remains the first-line cytostatic for the systemic treatment of disseminated STS.

In conclusion, the present in vitro study demonstrated that EGCG and silibinin inhibit the proliferation and viability of liposarcoma, synovial sarcoma, fibrosarcoma and pleomorphic sarcoma cells. Liposarcoma cell lines responded particularly well to EGCG while synovial sarcoma cell lines were more sensitive to silibinin. To the best of our knowledge, this is the first study to assess the effects of EGCG and silibinin on such a wide range of STS cell lines, including liposarcoma, synovial sarcoma, fibrosarcoma and pleomorphic sarcoma cells. EGCG and silibinin are not intended to supplant doxorubicin for the treatment of patients with disseminated STS; however, they may be a potential therapeutic option for patients who require palliative treatment but are considered unsuitable for chemotherapy. The present study provides evidence to support in vivo trials to examine the effects of these natural compounds on STS.


The present study was supported by a FoRUM grant from the Ruhr-University Bochum (Bochum, Germany; grant no. K090-15).


1. Hoos A, Lewis JJ, Brennan MF. Weichgewebssarkome-prognostische Faktoren und multimodale Therapie. Der Chirurg. 2000;71:787–794. doi: 10.1007/s001040051137. [PubMed] [Cross Ref]
2. Patrikidou A, Domont J, Cioffi A, Le Cesne A. Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol. 2011;12:21–31. doi: 10.1007/s11864-011-0145-5. [PubMed] [Cross Ref]
3. Kaushal A, Citrin D. The role of radiation therapy in the management of sarcomas. Surg Clin North Am. 2008;88(viii):629–646. [PMC free article] [PubMed]
4. O'Brien GC, Cahill RA, Bouchier-Hayes DJ, Redmond HP. Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma. Ir J Med Sci. 2006;175:10–14. doi: 10.1007/BF03168992. [PubMed] [Cross Ref]
5. Solomon LR, Cheesbrough JS, Bhargava R, Mitsides N, Heap M, Green G, Diggle P. Observational study of need for thrombolytic therapy and incidence of bacteremia using taurolidine-citrate-heparin, taurolidine-citrate and heparin catheter locks in patients treated with hemodialysis. Semin Dial. 2012;25:233–238. doi: 10.1111/j.1525-139X.2011.00951.x. [PubMed] [Cross Ref]
6. Karavasilis V, Seddon BM, Ashley S, Al-Muderis O, Fisher C, Judson I. Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: Retrospective analysis and identification of prognostic factors in 488 patients. Cancer. 2008;112:1585–1591. doi: 10.1002/cncr.23332. [PubMed] [Cross Ref]
7. Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF. Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma. Cancer. 1999;85:389–395. doi: 10.1002/(SICI)1097-0142(19990115)85:2<389::AID-CNCR17>3.3.CO;2-A. [PubMed] [Cross Ref]
8. Pezzi CM, Pollock RE, Evans HL, Lorigan JG, Pezzi TA, Benjamin RS, Romsdahl MM. Preoperative chemotherapy for soft-tissue sarcomas of the extremities. Ann Surg. 1990;211:476–481. doi: 10.1097/00000658-199004000-00015. [PubMed] [Cross Ref]
9. Di Paola Donato E, Nielsen OS. EORTC Soft Tissue and Bone Sarcoma Group: The EORTC soft tissue and bone sarcoma group. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2002;38:S138–S141. (Suppl 4) [PubMed]
10. Nedea EA, DeLaney TF. Sarcoma and skin radiation oncology. Hematol Oncol Clin North Am. 2006;20:401–429. doi: 10.1016/j.hoc.2006.01.017. [PubMed] [Cross Ref]
11. Brodowicz T, Schwameis E, Widder J, Amann G, Wiltschke C, Dominkus M, Windhager R, Ritschl P, Pötter R, Kotz R, Zielinski CC. Intensified adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: A prospective randomized feasibility trial. Sarcoma. 2000;4:151–160. doi: 10.1155/2000/126837. [PMC free article] [PubMed] [Cross Ref]
12. Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone A, Olmi P, Buonadonna A, Pignatti G, Barbieri E, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19:1238–1247. [PubMed]
13. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, Kerst JM, Sufliarsky J, Whelan J, Hohenberger P, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–423. doi: 10.1016/S1470-2045(14)70063-4. [PubMed] [Cross Ref]
14. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer. 2003;97:2869–2879. doi: 10.1002/cncr.11407. [PubMed] [Cross Ref]
15. Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2:14. doi: 10.1186/2045-3329-2-14. [PMC free article] [PubMed] [Cross Ref]
16. Jiang L, Tao C, He A, He X. Overexpression of miR-126 sensitizes osteosarcoma cells to apoptosis induced by epigallocatechin-3-gallate. World J Surg Oncol. 2014;12:383. doi: 10.1186/1477-7819-12-383. [PMC free article] [PubMed] [Cross Ref]
17. Lambert JD, Sang S, Hong J, Yang CS. Anticancer and anti-inflammatory effects of cysteine metabolites of the green tea polyphenol, (−)-epigallocatechin-3-gallate. J Agric Food Chem. 2010;58:10016–10019. doi: 10.1021/jf102311t. [PMC free article] [PubMed] [Cross Ref]
18. Kalaiselvi P, Rajashree K, Bharathi Priya L, Padma VV. Cytoprotective effect of epigallocatechin-3-gallate against deoxynivalenol-induced toxicity through anti-oxidative and anti-inflammatory mechanisms in HT-29 cells. Food Chem Toxicol. 2013;56:110–118. doi: 10.1016/j.fct.2013.01.042. [PubMed] [Cross Ref]
19. Deng YT, Lin JK. EGCG inhibits the invasion of highly invasive CL1-5 lung cancer cells through suppressing MMP-2 expression via JNK signaling and induces G2/M arrest. J Agric Food Chem. 2011;59:13318–13327. doi: 10.1021/jf204149c. [PubMed] [Cross Ref]
20. Kobalka AJ, Keck RW, Jankun J. Synergistic anticancer activity of biologicals from green and black tea on DU 145 human prostate cancer cells. Cent Eur J Immunol. 2015;40:1–4. [PMC free article] [PubMed]
21. Park IJ, Lee YK, Hwang JT, Kwon DY, Ha J, Park OJ. Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose H2O2. Ann N Y Acad Sci. 2009;1171:538–544. doi: 10.1111/j.1749-6632.2009.04698.x. [PubMed] [Cross Ref]
22. Park JS, Khoi PN, Joo YE, Lee YH, Lang SA, Stoeltzing O, Jung YD. EGCG inhibits recepteur d'origine nantais expression by suppressing Egr-1 in gastric cancer cells. Int J Oncol. 2013;42:1120–1126. [PubMed]
23. Braicu C, Gherman CD, Irimie A, Berindan-Neagoe I. Epigallocatechin-3-Gallate (EGCG) inhibits cell proliferation and migratory behaviour of triple negative breast cancer cells. J Nanosci Nanotechnol. 2013;13:632–637. doi: 10.1166/jnn.2013.6882. [PubMed] [Cross Ref]
24. Zou C, Liu H, Feugang JM, Hao Z, Chow HH, Garcia F. Green tea compound in chemoprevention of cervical cancer. Int J Gynecol Cancer. 2010;20:617–624. doi: 10.1111/IGC.0b013e3181c7ca5c. [PMC free article] [PubMed] [Cross Ref]
25. Shanafelt TD, Call TG, Zent CS, Leis JF, LaPlant B, Bowen DA, Roos M, Laumann K, Ghosh AK, Lesnick C, et al. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2013;119:363–370. doi: 10.1002/cncr.27719. [PMC free article] [PubMed] [Cross Ref]
26. de la Torre R, de Sola S, Hernandez G, Farré M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, et al. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:801–810. doi: 10.1016/S1474-4422(16)30034-5. [PubMed] [Cross Ref]
27. Zhao H, Xie P, Li X, Zhu W, Sun X, Sun X, Chen X, Xing L, Yu J. A prospective phase II trial of EGCG in treatment of acute radiation-induced esophagitis for stage III lung cancer. Radiother Oncol. 2015;114:351–356. doi: 10.1016/j.radonc.2015.02.014. [PubMed] [Cross Ref]
28. Trudel D, Labbé DP, Araya-Farias M, Doyen A, Bazinet L, Duchesne T, Plante M, Grégoire J, Renaud MC, Bachvarov D, et al. A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer. Gynecol Oncol. 2013;131:357–361. doi: 10.1016/j.ygyno.2013.08.019. [PubMed] [Cross Ref]
29. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, Le C, Wu AH, Ursin G, Yuan JM, Kurzer MS. The safety of green tea extract supplementation in postmenopausal women at risk for breast cancer: Results of the Minnesota Green Tea Trial. Food Chem Toxicol. 2015;83:26–35. doi: 10.1016/j.fct.2015.05.019. [PMC free article] [PubMed] [Cross Ref]
30. Garcia FA, Cornelison T, Nuño T, Greenspan DL, Byron JW, Hsu CH, Alberts DS, Chow HH. Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia. Gynecol Oncol. 2014;132:377–382. doi: 10.1016/j.ygyno.2013.12.034. [PMC free article] [PubMed] [Cross Ref]
31. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011;82:1807–1821. doi: 10.1016/j.bcp.2011.07.093. [PMC free article] [PubMed] [Cross Ref]
32. Shanafelt TD, Call TG, Zent CS, LaPlant B, Bowen DA, Roos M, Secreto CR, Ghosh AK, Kabat BF, Lee MJ, et al. Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J Clin Oncol. 2009;27:3808–3814. doi: 10.1200/JCO.2008.21.1284. [PMC free article] [PubMed] [Cross Ref]
33. Mengs U, Pohl RT, Mitchell T. Legalon® SIL: The antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol. 2012;13:1964–1970. doi: 10.2174/138920112802273353. [PMC free article] [PubMed] [Cross Ref]
34. Flaig TW, Glodé M, Gustafson D, van Bokhoven A, Tao Y, Wilson S, Su LJ, Li Y, Harrison G, Agarwal R, et al. A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate. 2010;70:848–855. [PubMed]
35. Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, Pierson AS, Agarwal R, Glodé LM. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs. 2007;25:139–146. [PubMed]
36. Kaur M, Velmurugan B, Tyagi A, Deep G, Katiyar S, Agarwal C, Agarwal R. Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther. 2009;8:2366–2374. doi: 10.1158/1535-7163.MCT-09-0304. [PMC free article] [PubMed] [Cross Ref]
37. Singh RP, Agarwal R. Prostate cancer chemoprevention by silibinin: Bench to bedside. Mol Carcinog. 2006;45:436–442. doi: 10.1002/mc.20223. [PubMed] [Cross Ref]
38. Leon IE, Porro V, Di Virgilio AL, Naso LG, Williams PA, Bollati-Fogolín M, Etcheverry SB. Antiproliferative and apoptosis-inducing activity of an oxidovanadium (IV) complex with the flavonoid silibinin against osteosarcoma cells. J Biol Inorg Chem. 2014;19:59–74. doi: 10.1007/s00775-013-1061-x. [PubMed] [Cross Ref]
39. Vue B, Zhang S, Zhang X, Parisis K, Zhang Q, Zheng S, Wang G, Chen QH. Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations. Eur J Med Chem. 2016;109:36–46. doi: 10.1016/j.ejmech.2015.12.041. [PMC free article] [PubMed] [Cross Ref]
40. Duan WJ, Li QS, Xia MY, Tashiro S, Onodera S, Ikejima T. Silibinin activated p53 and induced autophagic death in human fibrosarcoma HT1080 cells via reactive oxygen species-p38 and c-Jun N-terminal kinase pathways. Biol Pharm Bull. 2011;34:47–53. doi: 10.1248/bpb.34.47. [PubMed] [Cross Ref]
41. Ghaly PE, El-Magd RM Abou, Churchill CD, Tuszynski JA, West FG. A new antiproliferative noscapine analogue: Chemical synthesis and biological evaluation. Oncotarget. 2016;7:40518–40530. [PMC free article] [PubMed]
42. Yang ZR, Liu M, Peng XL, Lei XF, Zhang JX, Dong WG. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro. Biochem Biophys Res Commun. 2012;421:627–633. doi: 10.1016/j.bbrc.2012.04.079. [PubMed] [Cross Ref]
43. Li S, He J, Li S, Cao G, Tang S, Tong Q, Joshi HC. Noscapine induced apoptosis via downregulation of survivin in human neuroblastoma cells having wild type or null p53. PloS One. 2012;7:e40076. doi: 10.1371/journal.pone.0040076. [PMC free article] [PubMed] [Cross Ref]
44. Quisbert-Valenzuela EO, Calaf GM. Apoptotic effect of noscapine in breast cancer cell lines. Int J Oncol. 2016;48:2666–2674. [PubMed]
45. Lopus M, Naik PK. Taking aim at a dynamic target: Noscapinoids as microtubule-targeted cancer therapeutics. Pharmacol Rep. 2015;67:56–62. doi: 10.1016/j.pharep.2014.09.003. [PubMed] [Cross Ref]
46. Mukkavilli R, Gundala SR, Yang C, Jadhav GR, Vangala S, Reid MD, Aneja R. Noscapine recirculates enterohepatically and induces self-clearance. Eur J Pharm Sci. 2015;77:90–99. doi: 10.1016/j.ejps.2015.05.026. [PMC free article] [PubMed] [Cross Ref]
47. Stratford EW, Castro R, Daffinrud J, Skårn M, Lauvrak S, Munthe E, Myklebost O. Characterization of liposarcoma cell lines for preclinical and biological studies. Sarcoma. 2012;2012:148614. [PMC free article] [PubMed]
48. Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willén H, Rydholm A, Mitelman F. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11) Genes, chromosomes cancer. 1992;5:278–285. doi: 10.1002/gcc.2870050403. [PubMed] [Cross Ref]
49. Kawai A, Naito N, Yoshida A, Morimoto Y, Ouchida M, Shimizu K, Beppu Y. Establishment and characterization of a biphasic synovial sarcoma cell line, SYO-1. Cancer Lett. 2004;204:105–113. doi: 10.1016/j.canlet.2003.09.031. [PubMed] [Cross Ref]
50. Xie Y, Skytting B, Nilsson G, Gasbarri A, Haslam K, Bartolazzi A, Brodin B, Mandahl N, Larsson O. SYT-SSX is critical for cyclin D1 expression in synovial sarcoma cells: A gain of function of the t(X;18)(p11.2;q11.2) translocation. Cancer Res. 2002;62:3861–3867. [PubMed]
51. Becerikli M, Jacobsen F, Rittig A, Köhne W, Nambiar S, Mirmohammadsadegh A, Stricker I, Tannapfel A, Wieczorek S, Epplen JT, et al. Growth rate of late passage sarcoma cells is independent of epigenetic events but dependent on the amount of chromosomal aberrations. Exp Cell Res. 2013;319:1724–1731. doi: 10.1016/j.yexcr.2013.03.023. [PubMed] [Cross Ref]
52. Kang HG, Jenabi JM, Liu XF, Reynolds CP, Triche TJ, Sorensen PH. Inhibition of the insulin-like growth factor I receptor by epigallocatechin gallate blocks proliferation and induces the death of Ewing tumor cells. Mol Cancer Ther. 2010;9:1396–1407. doi: 10.1158/1535-7163.MCT-09-0604. [PubMed] [Cross Ref]
53. Chougule MB, Patel AR, Jackson T, Singh M. Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer. PloS One. 2011;6:e17733. doi: 10.1371/journal.pone.0017733. [PMC free article] [PubMed] [Cross Ref]
54. Koval OA, Sakaeva GR, Fomin AS, Nushtaeva AA, Semenov DV, Kuligina EV, Gulyaeva LF, Gerasimov AV, Richter VA. Sensitivity of endometrial cancer cells from primary human tumor samples to new potential anticancer peptide lactaptin. J Cancer Res Ther. 2015;11:345–351. doi: 10.4103/0973-1482.157301. [PubMed] [Cross Ref]
55. Italiano A, Toulmonde M, Cioffi A, Penel N, Isambert N, Bompas E, Duffaud F, Patrikidou A, Lortal B, Le Cesne A, et al. Advanced well-differentiated/dedifferentiated liposarcomas: Role of chemotherapy and survival. Ann Oncol. 2012;23:1601–1607. doi: 10.1093/annonc/mdr485. [PubMed] [Cross Ref]
56. Italiano A, Garbay D, Cioffi A, Maki RG, Bui B. Advanced pleomorphic liposarcomas: Clinical outcome and impact of chemotherapy. Ann Oncol. 2012;23:2205–2206. doi: 10.1093/annonc/mds219. [PubMed] [Cross Ref]
57. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41:2853–2860. doi: 10.1016/j.ejca.2005.07.023. [PubMed] [Cross Ref]
58. Patel SR, Burgess MA, Plager C, Papadopoulos NE, Linke KA, Benjamin RS. Myxoid liposarcoma. Experience with chemotherapy. Cancer. 1994;74:1265–1269. doi: 10.1002/1097-0142(19940815)74:4<1265::AID-CNCR2820740414>3.0.CO;2-X. [PubMed] [Cross Ref]
59. Vlenterie M, Litière S, Rizzo E, Marréaud S, Judson I, Gelderblom H, Le Cesne A, Wardelmann E, Messiou C, Gronchi A, van der Graaf WT. Outcome of chemotherapy in advanced synovial sarcoma patients: Review of 15 clinical trials from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group; setting a new landmark for studies in this entity. Eur J Cancer. 2016;58:62–72. doi: 10.1016/j.ejca.2016.02.002. [PubMed] [Cross Ref]
60. Saeed NM, El-Naga RN, El-Bakly WM, Abdel-Rahman HM, Salah ElDin RA, El-Demerdash E. Epigallocatechin-3-gallate pretreatment attenuates doxorubicin-induced cardiotoxicity in rats: A mechanistic study. Biochem Pharmacol. 2015;95:145–155. doi: 10.1016/j.bcp.2015.02.006. [PubMed] [Cross Ref]
61. Khan MA, Singh M, Khan MS, Ahmad W, Najmi AK, Ahmad S. Alternative approach for mitigation of doxorubicin-induced cardiotoxicity using herbal agents. Curr Clin Pharmacol. 2014;9:288–297. doi: 10.2174/1574884709999140606162053. [PubMed] [Cross Ref]
62. Zheng J, Lee HC, Bin Sattar MM, Huang Y, Bian JS. Cardioprotective effects of epigallocatechin-3-gallate against doxorubicin-induced cardiomyocyte injury. Eur J Pharmacol. 2011;652:82–88. doi: 10.1016/j.ejphar.2010.10.082. [PubMed] [Cross Ref]
63. Li W, Nie S, Xie M, Chen Y, Li C, Zhang H. A major green tea component, (−)-epigallocatechin-3-gallate, ameliorates doxorubicin-mediated cardiotoxicity in cardiomyocytes of neonatal rats. J Agric Food Chem. 2010;58:8977–8982. doi: 10.1021/jf101277t. [PubMed] [Cross Ref]
64. Cheng T, Liu J, Ren J, Huang F, Ou H, Ding Y, Zhang Y, Ma R, An Y, Liu J, Shi L. Green tea catechin-based complex micelles combined with doxorubicin to overcome cardiotoxicity and multidrug resistance. Theranostics. 2016;6:1277–1292. doi: 10.7150/thno.15133. [PMC free article] [PubMed] [Cross Ref]
65. Stearns ME, Amatangelo MD, Varma D, Sell C, Goodyear SM. Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: Inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am J Pathol. 2010;177:3169–3179. doi: 10.2353/ajpath.2010.100330. [PubMed] [Cross Ref]
66. Chen L, Ye HL, Zhang G, Yao WM, Chen XZ, Zhang FC, Liang G. Autophagy inhibition contributes to the synergistic interaction between EGCG and doxorubicin to kill the hepatoma Hep3B cells. PloS One. 2014;9:e85771. doi: 10.1371/journal.pone.0085771. [PMC free article] [PubMed] [Cross Ref]
67. Liang G, Tang A, Lin X, Li L, Zhang S, Huang Z, Tang H, Li QQ. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int J Oncol. 2010;37:111–123. [PubMed]
68. Singh RP, Mallikarjuna GU, Sharma G, Dhanalakshmi S, Tyagi AK, Chan DC, Agarwal C, Agarwal R. Oral silibinin inhibits lung tumor growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor kappaB-mediated inducible chemoresistance. Clin Cancer Res. 2004;10:8641–8647. doi: 10.1158/1078-0432.CCR-04-1435. [PubMed] [Cross Ref]
69. Tyagi AK, Agarwal C, Chan DC, Agarwal R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep. 2004;11:493–499. [PubMed]
70. Tyagi AK, Singh RP, Agarwal C, Chan DC, Agarwal R. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin Cancer Res. 2002;8:3512–3519. [PubMed]
71. Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules. 2011;16:8601–8613. doi: 10.3390/molecules16108601. [PubMed] [Cross Ref]
72. Chlopcíková S, Psotová J, Miketová P, Simánek V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother Res. 2004;18:107–110. doi: 10.1002/ptr.1415. [PubMed] [Cross Ref]
73. Psotová J, Chlopcíková S, Grambal F, Simánek V, Ulrichová J. Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res. 2002;16:S63–S67. doi: 10.1002/ptr.811. (Suppl 1) [PubMed] [Cross Ref]

Articles from Molecular Medicine Reports are provided here courtesy of Spandidos Publications