Skip to main content

Advertisement

SpringerLink
Log in

Epigallocatechin-3-gallate potentiates curcumin’s ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Uterine leiomyosarcoma (LMS) has an unfavorable response to standard chemotherapeutic regimens. Two natural occurring compounds, curcumin and epigallocatechin gallate (EGCG), are reported to have anti-cancer activity. We previously reported that curcumin reduced uterine LMS cell proliferation by targeting the AKT–mTOR pathway. However, challenges remain in overcoming curcumin’s low bioavailability.

Methods

The human LMS cell line SKN was used. The effect of EGCG, curcumin or their combination on cell growth was detected by MTS assay. Their effect on AKT, mTOR, and S6 was detected by Western blotting. The induction of apoptosis was determined by Western blotting using cleaved-PARP specific antibody, caspase-3 activity and TUNEL assay. Intracellular curcumin level was determined by a spectrophotometric method. Antibody against EGCG cell surface receptor, 67-kDa laminin receptor (67LR), was used to investigate the role of the receptor in curcumin’s increased potency by EGCG.

Results

In this study, we showed that the combination of EGCG and curcumin significantly reduced SKN cell proliferation more than either drug alone. The combination inhibited AKT, mTOR, and S6 phosphorylation, and induced apoptosis at a much lower curcumin concentration than previously reported. EGCG enhanced the incorporation of curcumin. 67LR antibody partially rescued cell proliferation suppression by the combination treatment, but was not involved in the EGCG-enhanced intracellular incorporation of curcumin.

Conclusions

EGCG significantly lowered the concentration of curcumin required to inhibit the AKT–mTOR pathway, reduce cell proliferation and induce apoptosis in uterine LMS cells by enhancing intracellular incorporation of curcumin, but the process was independent of 67LR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Leitao MM, Sonoda Y, Brennan MF et al (2003) Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 91:209–212

    Article  PubMed  Google Scholar 

  2. Naaman Y, Shveiky D, Ben-Shachar I et al (2011) Uterine sarcoma: prognostic factors and treatment evaluation. Isr Med Assoc J 13:76–79

    PubMed  Google Scholar 

  3. Muss HB, Bundy B, DiSaia PJ et al (1985) Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 55:1648–1653

    Article  PubMed  CAS  Google Scholar 

  4. Omura GA, Major FJ, Blessing JA et al (1983) A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 52:626–632

    Article  PubMed  CAS  Google Scholar 

  5. Sutton G, Blessing JA, Malfetano JH (1996) Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group Study. Gynecol Oncol 62:226–229

    Article  PubMed  CAS  Google Scholar 

  6. Piver MS, Lele SB, Marchetti DL et al (1988) Effect of adjuvant chemotherapy on time to recurrence and survival of stage I uterine sarcomas. J Surg Oncol 38:233–239

    Article  PubMed  CAS  Google Scholar 

  7. Omura GA, Blessing JA, Major F et al (1985) A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 3:1240–1245

    PubMed  CAS  Google Scholar 

  8. Hernando E, Charytonowicz E, Dudas ME et al (2007) The AKT–mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13:748–753

    Article  PubMed  CAS  Google Scholar 

  9. Amant F, Coosemans A, Debiec-Rychter M et al (2009) Clinical management of uterine sarcomas. Lancet Oncol 10:1188–1198

    Article  PubMed  Google Scholar 

  10. Sarbassov DD, Ali SM, Kim DH et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302

    Article  PubMed  CAS  Google Scholar 

  11. Breuleux M, Klopfenstein M, Stephan C et al (2009) Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 8:742–753

    Article  PubMed  CAS  Google Scholar 

  12. Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  13. Lambert JD, Yang CS (2003) Mechanisms of cancer prevention by tea constituents. J Nutr 133:3262S–3267S

    PubMed  CAS  Google Scholar 

  14. Yang CS, Sang S, Lambert JD et al (2006) Possible mechanisms of the cancer-preventive activities of green tea. Mol Nutr Food Res 50:170–175

    Article  PubMed  CAS  Google Scholar 

  15. Brown MD (1999) Green tea (Camellia sinensis) extract and its possible role in the prevention of cancer. Altern Med Rev 4:360–370

    PubMed  CAS  Google Scholar 

  16. Bettuzzi S, Brausi M, Rizzi F et al (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 66:1234–1240

    Article  PubMed  CAS  Google Scholar 

  17. Toda M, Okubo S, Ikigai H et al (1990) Antibacterial and anti-hemolysin activities of tea catechins and their structural relatives. Nippon Saikingaku Zassi 45:561–566

    Article  CAS  Google Scholar 

  18. Lin YL, Lin JK (1997) (−)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-κB. Mol Pharmacol 52:465–472

    PubMed  CAS  Google Scholar 

  19. Maeda-Yamamoto M, Inagaki N, Kitaura J et al (2004) O-Methylated catechins from tea leaves inhibit multiple protein kinases in mast cells. J Immunol 172:4486–4492

    PubMed  CAS  Google Scholar 

  20. Wheeler DS, Catravas JD, Odoms K et al (2004) Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1β-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134:1039–1044

    PubMed  CAS  Google Scholar 

  21. Yang F, Oz HS, Barve S et al (2001) The green tea polyphenol (−)-epigallocatechin-3-gallate blocks nuclear factor-κB activation by inhibiting IκB kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol 60:528–533

    PubMed  CAS  Google Scholar 

  22. Van Aller GS, Carson JD, Tang W et al (2011) Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochem Biophys Res Co 406:194–199

    Article  Google Scholar 

  23. Anand P, Sundaram C, Jhurani S et al (2008) Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett 267:133–164

    Article  PubMed  CAS  Google Scholar 

  24. Wong TF, Takeda T, Li B et al (2011) Curcumin disrupts uterine leiomyosarcoma cells through AKT–mTOR pathway inhibition. Gynecol Oncol 122:141–148

    Article  PubMed  CAS  Google Scholar 

  25. Somers-Edgar TJ, Scandlyn MJ, Stuart EC et al (2008) The combination of epigallocatechin gallate and curcumin suppresses ERα-breast cancer cell growth in vitro and in vivo. Int J Cancer 122:1966–1971

    Article  PubMed  CAS  Google Scholar 

  26. Ghosh AK, Kay NE, Secreto CR et al (2009) Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res 15:1250–1258

    Article  PubMed  CAS  Google Scholar 

  27. Saha A, Kuzuhara T, Echigo N et al (2010) New role of (−)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin. Cancer Prev Res 3:953–962

    Article  CAS  Google Scholar 

  28. Tachibana H, Koga K, Fujimura Y et al (2004) A receptor of green tea polyphenol EGCG. Nat Struct Mol Biol 11:380–381

    Article  PubMed  CAS  Google Scholar 

  29. Ishiwata I, Nozawa S, Nagal S et al (1977) Establishment of a human leiomyosarcoma cell line. Cancer Res 37:658–664

    PubMed  CAS  Google Scholar 

  30. Byun EH, Fujimura Y, Yamada K et al (2010) TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. J Immunol 185:33–45

    Article  Google Scholar 

  31. Holy EW, Stänpfli SF, Akhmedov A et al (2010) Laminin receptor activation inhibits endothelial tissue factor expression. J Mol Cell Cardiol 48:1138–1145

    Article  PubMed  CAS  Google Scholar 

  32. Kuesap J, Li B, Satarug S et al (2008) Prostaglandin D2 induces heme oxygenase-1 in human retinal pigment epithelial cells. Biochem Biophys Res Commun 367:413–419

    Article  PubMed  CAS  Google Scholar 

  33. Scott DW, Loo G (2007) Curcumin-induced GADD153 upregulation: modulation by glutathione. J Cell Biochem 101:307–320

    Article  PubMed  CAS  Google Scholar 

  34. Shoba G, Joy D, Joseph T et al (1998) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64:353–356

    Article  PubMed  CAS  Google Scholar 

  35. Telang N, Katdare M (2007) Combinatorial prevention of carcinogenic risk in a model for familial colon cancer. Oncol Rep 17:909–914

    PubMed  CAS  Google Scholar 

  36. Wan X, Harkavy B, Shen N et al (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932–1940

    Article  PubMed  CAS  Google Scholar 

  37. Tewari M, Quan LT, O’Rourke K et al (1995) Yama/CPP32β, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose)polymerase. Cell 81:801–809

    Article  PubMed  CAS  Google Scholar 

  38. Nagata S (2000) Apoptotic DNA fragmentation. Exp Cell Res 256:12–18

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported, in part, by grants from the Japanese Ministry of Education, Science, Sports, and Culture, Tokyo, Japan (23592430).

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Seiryomachi 1-1, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Akiko Kondo, Takashi Takeda, Mari Kitamura, Tze Fang Wong & Nobuo Yaegashi

  2. Department of Traditional Asian Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

    Takashi Takeda, Bin Li, Kenji Tsuiji & Nobuo Yaegashi

Authors
  1. Akiko Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Tsuiji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mari Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tze Fang Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobuo Yaegashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Takeda.

About this article

Cite this article

Kondo, A., Takeda, T., Li, B. et al. Epigallocatechin-3-gallate potentiates curcumin’s ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis. Int J Clin Oncol 18, 380–388 (2013). https://doi.org/10.1007/s10147-012-0387-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-012-0387-7

Keywords

Search

Navigation