Skip to main content
SpringerLink
Log in

Kuguacin J isolated from bitter melon leaves modulates paclitaxel sensitivity in drug-resistant human ovarian cancer cells

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

We previously reported the multidrug resistance-reversing ability of kuguacin J (KJ) in cervical cancer cells via the inhibition of P-glycoprotein (P-gp) function. This study investigated whether KJ could promote cisplatin- and paclitaxel (PTX)-induced cancer cell death in drug-resistance human ovarian cancer cells (SKOV3). Cytotoxicity testing showed that SKOV3 was more resistant to cisplatin and PTX compared to drug-sensitive human ovarian cancer cells (A2780). The cytotoxicity of PTX was significantly increased in SKOV3 cells when co-treated with KJ. We found that enhancement of PTX toxicity in the cells was not related to P-gp inhibition. To elucidate the mechanism by which KJ increases PTX sensitivity, the expression of cell death involving proteins was analyzed by Western blot analysis. The results showed that PTX treatment increased the level of an anti-apoptotic protein, survivin, which may be involved in drug resistance in SKOV3. The co-treatment with PTX and KJ dramatically decreased the level of survivin and markedly induced cleavage of PARP and caspase-3, which are apoptotic-induced molecules. These findings may support the use of KJ as an effective chemosensitizer in combination with conventional chemotherapy to promote PTX sensitization in ovarian cancer patients.

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

Similar content being viewed by others

References

  1. Dunton CJ (1997) New options for the treatment of advanced ovarian cancer. Semin Oncol 24:S5-2–S5-11

    Google Scholar 

  2. ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I et al (1997) Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15:2183–2193

    Article  Google Scholar 

  3. Rose PG, Blessing JA, Mayer AR, Homesley HD (1998) Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 16:405–410

    Article  CAS  Google Scholar 

  4. Markman M, Blessing JA, Moore D, Ball H, Lentz SS (1998) Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial. Gynecol Oncol 69:226–229

    Article  CAS  Google Scholar 

  5. Shapiro JD, Millward MJ, Rischin D, Michael M, Walcher V, Francis PA et al (1996) Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 63:89–93

    Article  CAS  Google Scholar 

  6. Gershenson DM, Burke TW, Morris M, Bast RC, Guaspari A, Hohneker J et al (1998) A phase I study of a daily x3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer. Gynecol Oncol 70:404–409

    Article  CAS  Google Scholar 

  7. Wilson TR, Longley DB, Johnston PG (2006) Chemoresistance in solid tumours. Ann Oncol 17(Suppl 10):x315–324

    Article  Google Scholar 

  8. Kigawa J (2013) New strategy for overcoming resistance to chemotherapy of ovarian cancer. Yonago Acta Medica 56:43–50

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Limtrakul P, Khantamat O, Pintha K (2004) Inhibition of P-glycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract. Cancer Chemother Pharmacol 54:525–530

    Article  Google Scholar 

  10. Pitchakarn P, Ogawa K, Suzuki S, Takahashi S, Asamoto M, Chewonarin T et al (2010) Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo. Cancer Sci 101:2234–2240

    Article  CAS  Google Scholar 

  11. Pitchakarn P, Suzuki S, Ogawa K, Pompimon W, Takahashi S, Asamoto M et al (2011) Induction of G1 arrest and apoptosis in androgen-dependent human prostate cancer by Kuguacin J, a triterpenoid from Momordica charantia leaf. Cancer Lett 306:142–150

    Article  CAS  Google Scholar 

  12. Pitchakarn P, Ohnuma S, Pintha K, Pompimon W, Ambudkar SV, Limtrakul P (2012) Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance. J Nutr Biochem. 23(1): 76−84

    Article  CAS  Google Scholar 

  13. Chen J, Tian R, Qiu M, Lu L, Zheng Y, Zhang Z (2008) Trinorcucurbitane and cucurbitane triterpenoids from the roots of Momordica charantia. Phytochemistry 69:1043–1048

    Article  CAS  Google Scholar 

  14. Chen JC, Liu WQ, Lu L, Qiu MH, Zheng YT, Yang LM et al (2009) Kuguacins F-S, cucurbitane triterpenoids from Momordica charantia. Phytochemistry 70:133–140

    Article  CAS  Google Scholar 

  15. Mekuria DB, Kashiwagi T, Tebayashi S, Kim CS (2005) Cucurbitane triterpenoid oviposition deterrent from Momordica charantia to the leafminer, Liriomyza trifolii. Biosci Biotechnol Biochem 69:1706–1710

    Article  CAS  Google Scholar 

  16. Puspawati N (2008) Isolation and identification momordicin I from leaves extract of Momordica charantia L. Jurnal Kimia 2:53–56

    Google Scholar 

  17. Graf U, van Schaik N (1992) Improved high bioactivation cross for the wing somatic mutation and recombination test in Drosophila melanogaster. Mutat Res 271:59–67

    Article  CAS  Google Scholar 

  18. Graf U, Würgler FE, Katz AJ, Frei H, Juon H, Hall CB et al (1984) Somatic mutation and recombination test in Drosophila melanogaster. Environ Mutagen 6:153–188

    Article  CAS  Google Scholar 

  19. Würgler FE, Graf U (1985) Mutagenicity testing with Drosophila melanogaster. Basic Life Sci 34:343–372

    PubMed  Google Scholar 

  20. Salzano G, Navarro G, Trivedi MS, De Rosa G, Torchilin VP (2015) Multifunctional polymeric micelles co-loaded with anti-survivin siRNA and paclitaxel overcome drug resistance in an animal model of ovarian cancer. Mol Cancer Ther 14:1075–1084

    Article  CAS  Google Scholar 

  21. Frei H, Würgler FE (1988) Statistical methods to decide whether mutagenicity test data from Drosophila assays indicate a positive, negative, or inconclusive result. Mutat Res 203:297–308

    Article  CAS  Google Scholar 

  22. Umsumarng S, Pintha K, Pitchakarn P, Sastraruji K, Sastraruji T, Ung AT et al (2013) Inhibition of P-glycoprotein mediated multidrug resistance by stemofoline derivatives. Chem Pharm Bull 61:399–404

    Article  CAS  Google Scholar 

  23. Thomas H, Coley HM (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10:159–165

    Article  Google Scholar 

  24. Ling X, Bernacki RJ, Brattain MG, Li F (2004) Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest. J Biol Chem 279:15196–15203

    Article  CAS  Google Scholar 

  25. Laohavechvanich P, Kangsadalampai K, Tirawanchai N, Ketterman AJ (2006) Effect of different Thai traditional processing of various hot chili peppers on urethane-induced somatic mutation and recombination in Drosophila melanogaster: assessment of the role of glutathione transferase activity. Food Chem Toxicol 44:1348–1354

    Article  CAS  Google Scholar 

  26. Zimmerli B, Schlatter J (1991) Ethyl carbamate: analytical methodology, occurrence, formation, biological activity and risk assessment. Mutat Res 259:325–350

    Article  CAS  Google Scholar 

  27. Davidson B, Trope CG (2014) Ovarian cancer: diagnostic, biological and prognostic aspects. Women’s Health 10:519–533

    CAS  PubMed  Google Scholar 

  28. Gabra H (2014) Introduction to managing patients with recurrent ovarian cancer. EJC Suppl 12:2–6

    Article  Google Scholar 

  29. Khan N, Adhami VM, Mukhtar H (2010) Apoptosis by dietary agents for prevention and treatment of prostate cancer. Endocr Relat Cancer 17:R39–52

    Article  CAS  Google Scholar 

  30. Thangapazham RL, Sharma A, Maheshwari RK (2006) Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J 8:E443–449

    Article  CAS  Google Scholar 

  31. Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L et al (2002) Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci 59:1406–1412

    Article  CAS  Google Scholar 

  32. Kar R, Palanichamy JK, Banerjee A, Chattopadhyay P, Jain SK, Singh N (2015) Survivin siRNA increases sensitivity of primary cultures of ovarian cancer cells to paclitaxel. Clin Transl Oncol 17:737–742

    Article  CAS  Google Scholar 

  33. Dong Z, Yang L, Lai D (2013) KLF5 strengthens drug resistance of ovarian cancer stem-like cells by regulating survivin expression. Cell Prolif 46:425–435

    Article  CAS  Google Scholar 

  34. Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:8581–8589

    Article  CAS  Google Scholar 

  35. Yasuda S, Yogosawa S, Izutani Y, Nakamura Y, Watanabe H, Sakai T (2010) Cucurbitacin B induces G2 arrest and apoptosis via a reactive oxygen species-dependent mechanism in human colon adenocarcinoma SW480 cells. Mol Nutr Food Res 54:559–565

    Article  CAS  Google Scholar 

  36. Zhang M, Hettiarachchy NS, Horax R, Chen P, Over KF (2009) Effect of maturity stages and drying methods on the retention of selected nutrients and phytochemicals in bitter melon (Momordica charantia) leaf. J Food Sci 74:C441–448

    Article  CAS  Google Scholar 

  37. Lin JP, Yang JS, Lu CC, Chiang JH, Wu CL, Lin JJ et al (2009) Rutin inhibits the proliferation of murine leukemia WEHI-3 cells in vivo and promotes immune response in vivo. Leuk Res 33:823–828

    Article  CAS  Google Scholar 

  38. Luo H, Jiang BH, King SM, Chen YC (2008) Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids. Nutr Cancer 60:800–809

    Article  CAS  Google Scholar 

  39. Martinez Conesa C, Vicente Ortega V, Yanez Gascon MJ, Alcaraz Banos M, Canteras Jordana M, Benavente-Garcia O et al (2005) Treatment of metastatic melanoma B16F10 by the flavonoids tangeretin, rutin, and diosmin. J Agric Food Chem 53:6791–6797

    Article  CAS  Google Scholar 

  40. Prakash G, Hosetti BB, Dhananjaya BL (2014) Antimutagenic effect of Dioscorea pentaphylla on genotoxic effect induced by methyl methanesulfonate in the Drosophila wing spot test. Toxicol Int 21:258–263

    Article  CAS  Google Scholar 

  41. Guterres ZR, Zanetti TA, Sennes-Lopes TF, da Silva AF (2015) Genotoxic and antigenotoxic potential of Momordica charantia Linn (Cucurbitaceae) in the wing spot test of Drosophila melanogaster. J Med Food 18:1136–1142

    Article  CAS  Google Scholar 

  42. Sarikaya R, Erciyas K, Kara MI, Sezer U, Erciyas AF, Ay S (2016) Evaluation of genotoxic and antigenotoxic effects of boron by the somatic mutation and recombination test (SMART) on Drosophila. Drug Chem Toxicol. 4:400−406

    Article  Google Scholar 

  43. Carmona ER, Escobar B, Vales G, Marcos R (2015) Genotoxic testing of titanium dioxide anatase nanoparticles using the wing-spot test and the comet assay in Drosophila. Mutat Res Genet Toxicol Environ Mutagen 778:12–21

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Thailand Research Fund (MRG No. 5580128), the Office of the Higher Education Commission, Thailand, the National Research Council of Thailand, the Faculty of Medicine Research Fund, Faculty of Medicine, Center of Excellent in Entomology and Application of Chiang Mai University, Chiang Mai University, and Grants-in-Aid from JSPS Core to-Core Program, B. Asia-Africa Science Platforms. The authors gratefully thank Ms. Crystal A. Young, University of St. Thomas, USA, for proofreading.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Pornsiri Pitchakarn, Sonthaya Umsumarng, Sariya Mapoung, Wanisa Punfa & Pornngarm Limtrakul

  2. Food and Nutritional Toxicology Unit, Institute of Nutrition, Mahidol University, Nakhon Pathom, Thailand

    Pisamai Ting & Piya Temviriyanukul

  3. Laboratory of Natural Products, Department of Chemistry, Faculty of Science, Lampang Rajabhat University, Lampang, Thailand

    Wilart Pompimon

Authors
  1. Pornsiri Pitchakarn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonthaya Umsumarng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sariya Mapoung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pisamai Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Piya Temviriyanukul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wanisa Punfa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wilart Pompimon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pornngarm Limtrakul
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Pornsiri Pitchakarn or Pornngarm Limtrakul.

Ethics declarations

Conflict of interest

The authors report no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pitchakarn, P., Umsumarng, S., Mapoung, S. et al. Kuguacin J isolated from bitter melon leaves modulates paclitaxel sensitivity in drug-resistant human ovarian cancer cells. J Nat Med 71, 693–702 (2017). https://doi.org/10.1007/s11418-017-1099-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-017-1099-0

Keywords

Search

Navigation