Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Silibinin Inhibits Proliferation, Induces Apoptosis and Causes Cell Cycle Arrest in Human Gastric Cancer MGC803 Cells Via STAT3 Pathway Inhibition

  • Wang, Yi-Xin (Department of Pharmacy, Sichuan Cancer Hospital) ;
  • Cai, Hong (Department of Pharmacy, Sichuan Cancer Hospital) ;
  • Jiang, Gang (Department of Pharmacy, Sichuan Cancer Hospital) ;
  • Zhou, Tian-Bao (Ningbo Hospital) ;
  • Wu, Hai (Department of Obstetrics and Gynecology, Suining Central Hospital)
  • Published : 2014.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: To investigate the effect of silibinin on proliferation and apoptosis in human gastric cancer cell line MGC803 and its possible mechanisms. Materials and Methods: Human gastric cancer cell line MGC803 cells were treated with various concentration of silibinin. Cellular viability was assessed by CCK-8 assay andapoptosis and cell cycle distribution by flow cytometry. Protein expression and mRNA of STAT3, and cell cycle and apoptosis regulated genes were detected by Western blotting and real-time polymerase chain reaction, respectively. Results: Silibinin inhibits growth of MGC803 cells in a dose- and time-dependent manner. Silibinin effectively induces apoptosis of MGC803 cells and arrests MGC803 cells in the G2/M phase of the cell cycle, while decreasing the protein expression of p-STAT3, and of STAT3 downstream target genes including Mcl-1, Bcl-xL, survivin at both protein and mRNA levels. In addition, silibinin caused an increase in caspase 3 and caspase 9 protein as well as mRNA levels. Silibinin caused G2/M phage arrest accompanied by a decrease in CDK1 and Cyclin B1 at protein and mRNA levels.. Conclusions: These results suggest that silibinin inhibits the proliferation of MGC803 cells, and it induces apoptosis and causes cell cycle arrest by down-regulating CDK1, cyclinB1, survivin, Bcl-xl, Mcl-1 and activating caspase 3 and caspase 9, potentially via the STAT3 pathway.

Keywords

References

  1. Agarwal C, Singh RP, Dhanalakshmi S, et al (2003). Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 22, 8271-82. https://doi.org/10.1038/sj.onc.1207158
  2. Ahmad A, Sarkar SH, Aboukameel A, et al (2012). Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis, 33, 2450-6. https://doi.org/10.1093/carcin/bgs290
  3. Ambrosini G, Adida C, Altieri DC (1997). A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med, 3, 917-21. https://doi.org/10.1038/nm0897-917
  4. Bollrath J, Phesse TJ, von Burstin VA, et al (2009). gp130- mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell, 15, 91-102. https://doi.org/10.1016/j.ccr.2009.01.002
  5. Chen XL, Chen XZ, Yang C, et al (2013). Docetaxel, cisplatin and fluorouracil (DCF) regimen compared with non-taxanecontaining palliative chemotherapy for gastric carcinoma, a systematic review and meta-analysis. PLoS One, 8, 60320. https://doi.org/10.1371/journal.pone.0060320
  6. Chetty C, Dontula R, Ganji PN, Gujrati M, Lakka SS (2012). SPARC expression induces cell cycle arrest via STAT3 signaling pathway in medulloblastoma cells. Biochem Biophys Res Commun, 417, 874-9. https://doi.org/10.1016/j.bbrc.2011.12.065
  7. Cheung CW, Gibbons N, Johnson DW, Nicol DL (2010). Silibinin--a promising new treatment for cancer. Anticancer Agents Med Chem, 10, 186-95. https://doi.org/10.2174/1871520611009030186
  8. Cufi S, Bonavia R, Vazquez-Martin A, et al (2013). Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFRmutant non-small-cell lung carcinoma cells. Food Chem Toxicol, 60, 360-8. https://doi.org/10.1016/j.fct.2013.07.063
  9. Cui JW, Li Y, Wang C, Cheng Y, Wei L (2012). Knockdown of a proliferation-inducing ligand (PRIL) suppresses the proliferation of gastric cancer cells. Asian Pac J Cancer Prev, 13, 633-36. https://doi.org/10.7314/APJCP.2012.13.2.633
  10. Deep G, Agarwal R (2010). Antimetastatic efficacy of silibinin, molecular mechanisms and therapeutic potential against cancer. Cancer Metastasis Rev, 29, 447-63. https://doi.org/10.1007/s10555-010-9237-0
  11. Deep G, Singh RP, Agarwal C, Kroll DJ, Agarwal R (2006). Silymarin and silibinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells, A comparison of flavanone silibinin with flavanolignan mixture silymarin. Oncogene, 25, 1053-69. https://doi.org/10.1038/sj.onc.1209146
  12. Devarajan E, Huang S (2009). STAT3 as a central regulator of tumor metastases. Curr Mol Med, 9, 626-33. https://doi.org/10.2174/156652409788488720
  13. Ding BB, Yu JJ, Yu RY, et al (2008). Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood, 111, 1515-23.
  14. Ececen T, Dost N, culhaci A, et al (2011). Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac J Cancer Prev, 12, 2697-704
  15. Feher J, Lengyel G (2012). Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol, 13, 210-7. https://doi.org/10.2174/138920112798868818
  16. Fischer U, Schulze-Osthoff K (2005). New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev, 57, 187-215. https://doi.org/10.1124/pr.57.2.6
  17. Fossey SL, Bear MD, Kisseberth WC, Pennell M, London CA (2011). Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines. BMC Cancer, 11, 125. https://doi.org/10.1186/1471-2407-11-125
  18. Ghasemi R, Ghaffari SH, Momeny M, et al (2013). Multitargeting and antimetastatic potentials of silibinin in human HepG-2 and PLC/PRF/5 Hepatoma cells. Nutr Cancer, 65, 590-9. https://doi.org/10.1080/01635581.2013.770043
  19. Ghobrial IM, Witzig TE, Adjei AA (2005). Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin, 55, 178-94. https://doi.org/10.3322/canjclin.55.3.178
  20. Giraud AS, Menheniott TR, Judd LM (2012). Targeting STAT3 in gastric cancer. Expert Opin Ther Targets, 16, 889-901. https://doi.org/10.1517/14728222.2012.709238
  21. Gritsko T, Williams A, Turkson J, et al (2006). Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res, 12, 11-9. https://doi.org/10.1158/1078-0432.CCR-04-1752
  22. Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS (2007). Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res, 143, 58-65. https://doi.org/10.1016/j.jss.2007.03.080
  23. Hsu KW, Hsieh RH, Huang KH, et al (2012). Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression. Carcinogenesis, 33, 1459-67. https://doi.org/10.1093/carcin/bgs165
  24. Huang C, Huang R, Chang W, et al (2012). The expression and clinical significance of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma. Neoplasma, 59, 52-61. https://doi.org/10.4149/neo_2012_007
  25. Huang S, Chen M, Shen Y, et al (2012). Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. Cancer Lett, 315, 198-205. https://doi.org/10.1016/j.canlet.2011.10.011
  26. Huang WW, Yang JS, Lin MW, et al (2012). Cucurbitacin E induces G (2)/M phase arrest through STAT3/p53/ p21 signaling and provokes apoptosis via Fas/CD95 and mitochondria-dependent pathways in human bladder cancer T24 cells. Evid Based Complement Alternat Med, 2012, 952762.
  27. Hunter AM, LaCasse EC, Korneluk RG (2007). The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis, 12, 1543-68. https://doi.org/10.1007/s10495-007-0087-3
  28. Kang MH, Reynolds CP (2009). Bcl-2 inhibitors, targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res, 15, 1126-32. https://doi.org/10.1158/1078-0432.CCR-08-0144
  29. Karpeh MS Jr (2013). Palliative treatment and the role of surgical resection in gastric cancer. Dig Surg, 30, 174-80. https://doi.org/10.1159/000351177
  30. Kaur M, Velmurugan B, Tyagi A, et al (2009). Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther, 8, 2366-74. https://doi.org/10.1158/1535-7163.MCT-09-0304
  31. Kazem NK, Abolfazl A, Mohammad PM, Alireza A, Hassan D (2013). Inhibition of leptin and leptin receptor gene expression by silibinin-curcumin combination. Asian Pac J Cancer Prev, 14, 6595-99. https://doi.org/10.7314/APJCP.2013.14.11.6595
  32. Kim DY, Cha ST, Ahn DH, et al (2009). STAT3 expression in gastric cancer indicates a poor prognosis. J Gastroenterol Hepatol, 24, 646-51. https://doi.org/10.1111/j.1440-1746.2008.05671.x
  33. Kujawski M, Kortylewski M, et al (2008). Stat3 mediates myeloid cell- dependent tumor angiogenesis in mice. J Clin Invest, 118, 3367-77. https://doi.org/10.1172/JCI35213
  34. Lee SW, Ahn YY, Kim YS, et al (2012). The Immunohistochemical Expression of STAT3, Bcl-xL, and MMP-2 Proteins in Colon Adenoma and Adenocarcinoma. Gut Liver, 6, 45-51. https://doi.org/10.5009/gnl.2012.6.1.45
  35. Leung WK, Wu MS, Kakugawa Y (2008). Asia pacific working group on gastric cancer. screening for gastric cancer in Asia, current evidence and practice. Lancet Oncol, 9, 279-87. https://doi.org/10.1016/S1470-2045(08)70072-X
  36. Li L, Zeng J, Gao Y, He D (2010). Targeting silibinin in the antiproliferative pathway. Expert Opin Investig Drugs, 19, 243-55. https://doi.org/10.1517/13543780903533631
  37. Lin CJ, Sukarieh R, Pelletier J (2009). Silibinin inhibits translation initiation, implications for anticancer therapy. Mol Cancer Ther, 8, 1606-12. https://doi.org/10.1158/1535-7163.MCT-08-1152
  38. Lin CM, Chen YH, Ma HP, et al (2012). Silibinin inhibits the invasion of IL-6-stimulated colon cancer cells via selective JNK/AP-1/MMP-2 modulation in vitro. J Agric Food Chem, 60, 12451-7. https://doi.org/10.1021/jf300964f
  39. Liu DB, Hu GY, Long GX, Qiu H, Mei Q, Hu GQ (2012). Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation. Acta Pharmacol Sin, 33, 682-90. https://doi.org/10.1038/aps.2012.18
  40. Lu W, Lin C, King TD, Chen H, Reynolds RC, Li Y (2012). Silibinin inhibits Wnt/$\beta$-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell Signal, 24, 2291-6. https://doi.org/10.1016/j.cellsig.2012.07.009
  41. Malumbres M, Barbacid M (2009). Cell cycle, CDKs and cancer, a changing paradigm. Nat Rev Cancer, 9, 153-66. https://doi.org/10.1038/nrc2602
  42. Marzieh N, Nosratollah Z, Kazem NK, Mahdieh M (2013). Curcumin and silibinin inhibit telomerase expression in T47D human breast cancer cells. Asian Pac J Cancer Prev, 14, 3449-53. https://doi.org/10.7314/APJCP.2013.14.6.3449
  43. Masuda H, Fong CS, Ohtsuki C, Haraguchi T, Hiraoka Y (2011). Spatiotemporal regulations of Wee1 at the G2/M transition. Mol Biol Cell, 22, 555-69. https://doi.org/10.1091/mbc.E10-07-0644
  44. Masuda M, Suzui M, Yasumatu R, et al (2002). Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res, 62, 3351-5.
  45. Mateen S, Raina K, Agarwal R (2013). Chemopreventive and anti-cancer efficacy of silibinin against growth and progression of lung cancer. Nutr Cancer, 65, 3-11. https://doi.org/10.1080/01635581.2013.785004
  46. Mateen S, Raina K, Jain AK, et al (2012). Epigenetic modifications and p21- cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics, 7, 1161-72. https://doi.org/10.4161/epi.22070
  47. Mateen S, Tyagi A, Agarwal C, Singh RP, Agarwal R (2010). Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators. Mol Carcinog, 49, 247-58.
  48. McDonald ER 3rd, El-Deiry WS (2000). Cell cycle control as a basis for cancer drug development (Review). Int J Oncol, 16, 871-86.
  49. Mita AC, Mita MM, Nawrocki ST, Giles FJ (2008). Survivin, key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res, 14, 5000-5. https://doi.org/10.1158/1078-0432.CCR-08-0746
  50. Morikawa T, Baba Y, Yamauchi M, et al (2011). STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res, 17, 1452-62. https://doi.org/10.1158/1078-0432.CCR-10-2694
  51. Niu G, Wright KL, Huang M, et al (2002). Constitutive Stat3 activity upregulates VEGF expression and tumor angiogenesis. Oncogene, 21, 2000-8. https://doi.org/10.1038/sj.onc.1205260
  52. Oh SJ, Jung SP, Han J, et al (2013). Silibinin inhibits TPAinduced cell migration and MMP-9 expression in thyroid and breast cancer cells. Oncol Rep, 29, 1343-8.
  53. Olivier G, Jonathon P (2010). Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis. Dev Cell, 18, 533-43. https://doi.org/10.1016/j.devcel.2010.02.013
  54. Owa T, Yoshino H, Yoshimatsu K, Nagasu T (2001). Cell cycle regulation in the G1 phase, a promising target for the development of new chemotherapeutic anticancer agents. Curr Med Chem, 8, 1487-503. https://doi.org/10.2174/0929867013371996
  55. Park MT, Lee SJ (2003). Cell cycle and cancer. J Biochem Mol Biol, 36, 60-5. https://doi.org/10.5483/BMBRep.2003.36.1.060
  56. Quoc Trung L, Espinoza JL, Takami A, Nakao S (2013). Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PLoS One, 8, 55183. https://doi.org/10.1371/journal.pone.0055183
  57. Rajamanickam S, Velmurugan B, Kaur M, Singh RP, Agarwal R (2010). Chemoprevention of intestinal tumorigenesis in APCmin/+ mice by silibinin. Cancer Res, 70, 2368-78. https://doi.org/10.1158/0008-5472.CAN-09-3249
  58. Santamaria D, Ortega S (2006). Cyclins and CDKS in development and cancer, lessons from genetically modified mice. Front Bio Sci, 11, 1164-88. https://doi.org/10.2741/1871
  59. Sato T, Neilson LM, Peck AR, et al (2011). Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res, 1, 347-55.
  60. Schwartz GK (2002). CDK inhibitors, cell cycle arrest versus apoptosis. Cell Cycle, 1, 122-3. https://doi.org/10.4161/cc.1.2.115
  61. Shi ZB, Zhao D, Huang YY, et al (2012). Discovery, synthesis, and evaluation of small-molecule signal transducer and activator of transcription 3 inhibitors. Chem Pharm Bull (Tokyo), 60, 1574-80.
  62. Singh N, Hussain S, Bharadwaj M, et al (2012). Overexpression of signal transducer and activator of transcription (STAT-3 and STAT-5) transcription factors and alteration of suppressor of cytokine signaling (SOCS-1) protein in prostate cancer. J Recept Signal Transduct Res, 32, 321-7. https://doi.org/10.3109/10799893.2012.733885
  63. Singh RP, Agarwal R (2004). Prostate cancer prevention by silibinin. Curr Cancer Drug Targets, 4, 1-11. https://doi.org/10.2174/1568009043481605
  64. Stephanou A, Brar BK, Knight RA, Latchman DS (2000). Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ, 7, 329-30. https://doi.org/10.1038/sj.cdd.4400656
  65. Sun M, Liu C, Nadiminty N, et al (2012). Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate, 72, 82-9. https://doi.org/10.1002/pros.21409
  66. Taylor WR, Stark GR (2001). Regulation of the G2/M transition by p53. Oncogene, 20, 1803-15. https://doi.org/10.1038/sj.onc.1204252
  67. Tyagi A, Agarwal C, Agarwal R (2002). The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/ p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells. Cell Cycle, 1, 137-42.
  68. Tyagi A, Agarwal C, Harrison G, Glode LM, Agarwal R (2004). Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKICDK- cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis, 25, 1711-20. https://doi.org/10.1093/carcin/bgh180
  69. Tyagi AK, Singh RP, Agarwal C, Chan DC, Agarwal R (2002). Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin Cancer Res, 8, 3512-9.
  70. Van Cutsem E, Van de Velde C, Roth A (2008). European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group. Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group. Eur J Cancer, 44, 182-94. https://doi.org/10.1016/j.ejca.2007.11.001
  71. Verschoyle RD, Greaves P, Patel K, et al (2008). Evaluation of the cancer chemopreventive efficacy of silibinin in genetic mouse models of prostate and intestinal carcinogenesis, relationship with silibinin levels. Eur J Cancer, 44, 898-906. https://doi.org/10.1016/j.ejca.2008.02.020
  72. Wang J, Chen S, Xu S, et al (2012). In vivo induction of apoptosis by fucoxanthin, a marine carotenoid, associated with downregulating STAT3/EGFR signaling in sarcoma 180 (S180) xenografts-bearing mice. Mar Drugs, 10, 2055-68. https://doi.org/10.3390/md10092055
  73. Wang YJ, Niu XP, Li Y, Zhen H, Ma YJ (2013). Effects of celecoxib on cycle kinetics of gastric cancer cells and protein expression of cytochrome c and caspase-9. Asian Pac J Cancer Prev, 14, 2343-47. https://doi.org/10.7314/APJCP.2013.14.4.2343
  74. Williams GH, Stoeber K (2012). The cell cycle and cancer. J Pathol, 226, 352-64. https://doi.org/10.1002/path.3022
  75. Wu KJ, Zeng J, Zhu GD, et al (2009). Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression. Acta Pharmacol Sin, 30, 1162-8. https://doi.org/10.1038/aps.2009.94
  76. Xiong H, Du W, Wang JL, et al (2012). Constitutive activation of STAT3 is predictive of poor prognosis in human gastric cancer. J Mol Med (Berl), 90, 1037-46. https://doi.org/10.1007/s00109-012-0869-0
  77. Yakata Y, Nakayama T, Yoshizaki A, et al (2007). Expression of p-STAT3 in human gastric carcinoma, significant correlation in tumour invasion and prognosis. Int J Oncol, 30, 437-42.
  78. Yang C, Lee H, Pal S, et al (2013). B cells Promote tumor progression via STAT3 regulated- angiogenesis. PLoS One, 8, 64159. https://doi.org/10.1371/journal.pone.0064159
  79. Yi Qin, Jing Chen, Li Li (2012). Exogenous morphine inhibits human gastric cancer MGC-803 cell growth by cell cycle arrest and apoptosis induction. Asian Pac J Cancer Prev, 13, 1377-82. https://doi.org/10.7314/APJCP.2012.13.4.1377
  80. Zhang HQ, He B, Fang N (2013). Autophagy inhibition sensitizes cisplatin cytotoxicity in human gastric cancer cell line sgc7901. Asian Pac J Cancer Prev, 14, 4685-88. https://doi.org/10.7314/APJCP.2013.14.8.4685
  81. Zhang X, Yue P, Page BD, et al (2012). Orally bioavailable smallmolecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci USA, 109, 9623-8. https://doi.org/10.1073/pnas.1121606109

Cited by

  1. Rutin mediated targeting of signaling machinery in cancer cells vol.14, pp.1, 2014, https://doi.org/10.1186/s12935-014-0124-6
  2. Fangchinoline inhibits the proliferation of SPC-A-1 lung cancer cells by blocking cell cycle progression vol.11, pp.2, 2015, https://doi.org/10.3892/etm.2015.2915
  3. Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways vol.16, pp.5, 2015, https://doi.org/10.7314/APJCP.2015.16.5.2087
  4. Silibinin suppresses NPM-ALK, potently induces apoptosis and enhances chemosensitivity in ALK-positive anaplastic large cell lymphoma pp.1029-2403, 2015, https://doi.org/10.3109/10428194.2015.1068306
  5. Anticancer effect of cucurbitacin B on MKN-45 cells via inhibition of the JAK2/STAT3 signaling pathway vol.12, pp.4, 2016, https://doi.org/10.3892/etm.2016.3670
  6. mRNA Expression of Bax, Bcl-2, p53, Cathepsin B, Caspase-3 and Caspase-9 in the HepG2 Cell Line Following Induction by a Novel Monoclonal Ab Hep88 mAb: Cross-Talk for Paraptosis and Apoptosis vol.17, pp.2, 2016, https://doi.org/10.7314/APJCP.2016.17.2.703
  7. Ginsenoside-Rh2 Inhibits Proliferation and Induces Apoptosis of Human Gastric Cancer SGC-7901 Side Population Cells vol.17, pp.4, 2016, https://doi.org/10.7314/APJCP.2016.17.4.1817
  8. HM015k, a Novel Silybin Derivative, Multi-Targets Metastatic Ovarian Cancer Cells and Is Safe in Zebrafish Toxicity Studies vol.8, pp.1663-9812, 2017, https://doi.org/10.3389/fphar.2017.00498
  9. EHHM, a novel phenolic natural product from Livistona chinensis, induces autophagy-related apoptosis in hepatocellular carcinoma cells vol.12, pp.5, 2016, https://doi.org/10.3892/ol.2016.5178
  10. Extracellular matrix degradation products downregulate neoplastic esophageal cell phenotype pp.1937-335X, 2019, https://doi.org/10.1089/ten.TEA.2018.0105