Skip to main content

Advertisement

SpringerLink
Log in

18beta-Glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The purpose of the present study was to evaluate the anti-tumor effects of 18beta-glycyrrhetinic acid (GA), a natural compound extracted from liquorice, against pituitary adenoma and its underlying mechanisms in cultured cells and mouse model of xenografted tumor. GA induced cellular damage in rat pituitary adenoma-derived MMQ and GH3 cells, manifested as reduced cell viability, increased lactate dehydrogenase release, elevated intracellular reactive oxygen species (ROS) and Ca2+ concentration. GA also caused G0/G1 phase arrest, increased apoptosis rate and increased mitochondrial membrane permeabilization by suppressing the mitochondrial membrane potential and down-regulating a ratio of B cell lymphoma 2 (Bcl-2) and Bax. GA activated calcium/calmodulin-dependent protein kinase II (CaMKII), c-Jun N-terminal kinase (JNK) and P38; but these activating effects were attenuated by pretreatment with N-acetyl-l-cysteine, a ROS inhibitor. Pretreatment with KN93, a CaMKII inhibitor, also abolished the GA activation of JNK and P38. GA remarkably inhibited growth of pituitary adenoma grafted on nude mice. These results suggest that the anti-pituitary adenoma effect of GA is associated with its apoptotic actions by activating mitochondria-mediated ROS/mitogen-activated protein kinase pathways in particular CaMKII that may serve a linkage between ROS accumulation and the activation of JNK and P38. This study provides experimental evidence in the support of further developing GA as a chemotherapeutic agent for pituitary adenoma.

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. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S (1990) Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71:1427–1433

    Article  CAS  PubMed  Google Scholar 

  2. Biller BM, Luciano A, Crosignani PG, Molitch M, Olive D, Rebar R, Sanfilippo J, Webster J, Zacur H (1999) Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 44:1075–1084

    CAS  PubMed  Google Scholar 

  3. Yuan HN, Wang CY, Sze CW, Tong Y, Tan QR, Feng XJ, Liu RM, Zhang JZ, Zhang YB, Zhang ZJ (2008) A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J Clin Psychopharmacol 28:264–370. doi:10.1097/JCP.0b013e318172473c

    Article  CAS  PubMed  Google Scholar 

  4. Wang D, Wong HK, Zhang L, McAlonan GM, Wang XM, Sze SC, Feng YB, Zhang ZJ (2012) Not only dopamine D2 receptors involved in peony-glycyrrhiza decoction, an herbal preparation against antipsychotic-associated hyperprolactinemia. Prog Neuropsychopharmacol Biol Psychiatr 39:332–338. doi:10.1016/j.pnpbp.2012.07.005

    Article  CAS  Google Scholar 

  5. Agarwal MK, Iqbal M, Athar M (2005) Inhibitory effect of 18beta-glycyrrhetinic acid on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in mice. Redox Rep 10:151–157. doi:10.1179/135100005X57346

    Article  CAS  PubMed  Google Scholar 

  6. Jeong HG, You HJ, Park SJ, Moon AR, Chung YC, Kang SK, Chun HK (2002) Hepatoprotective effects of 18beta-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol Res 46:221–227

    Article  CAS  PubMed  Google Scholar 

  7. Matsui S, Matsumoto H, Sonoda Y, Ando K, Aizu-Yokota E, Sato T, Kasahara T (2004) Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int Immunopharmacol 4:1633–1644. doi:10.1016/j.intimp.2004.07.023

    Article  CAS  PubMed  Google Scholar 

  8. Lee CS, Yang JC, Kim YJ, Jang ER, Kim W, Myung SC (2010) 18beta-Glycyrrhetinic acid potentiates apoptotic effect of trichostatin A on human epithelial ovarian carcinoma cell lines. Eur J Pharmacol 649:354–361

    Article  CAS  PubMed  Google Scholar 

  9. Kuang P, Zhao W, Su W, Zhang Z, Zhang L, Liu J, Ren G, Yin Z, Wang X (2013) 18beta-Glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell-mediated immunosuppression in mice. Int J Cancer 132:1831–1841. doi:10.1002/ijc.27852

    Article  CAS  PubMed  Google Scholar 

  10. Sharma G, Kar S, Palit S, Das PK (2011) 18beta-Glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells. J Cell Physiol 227:1923–1931. doi:10.1002/jcp.22920

    Article  Google Scholar 

  11. Tsujimoto Y, Shimizu S (2007) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12:835–840. doi:10.1007/s10495-006-0525-7

    Article  CAS  PubMed  Google Scholar 

  12. Soliman D, Hamming KS, Matemisz LC, Light PE (2009) Reactive oxygen species directly modify sodium-calcium exchanger activity in a splice variant-dependent manner. J Mol Cell Cardiol 47:595–602

    Article  CAS  PubMed  Google Scholar 

  13. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15. doi:10.1002/jcp.10119

    Article  CAS  PubMed  Google Scholar 

  14. Yong XU (2007) Effect of serum containing stir-baked fructus hordei germinatus on secretion of NGF and PRL by Rat MMQ pituitary adenoma cell line in vitro. Chin J Clin Neurosurg 12:736–738

    Google Scholar 

  15. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  16. Legrand C, Bour JM, Jacob C, Capiaumont J, Martial A, Marc A, Wudtke M, Kretzmer G, Demangel C, Duval D et al (1992) Lactate dehydrogenase (LDH) activity of the cultured eukaryotic cells as marker of the number of dead cells in the medium [corrected]. J Biotechnol 25:231–243

    Article  CAS  PubMed  Google Scholar 

  17. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C (1995) A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 184:39–51

    Article  CAS  PubMed  Google Scholar 

  18. Soletti RC, del Barrio L, Daffre S, Miranda A, Borges HL, Moura-Neto V, Lopez MG, Gabilan NH (2010) Peptide gomesin triggers cell death through L-type channel calcium influx, MAPK/ERK, PKC and PI3 K signaling and generation of reactive oxygen species. Chem Biol Interact 186:135–143

    Article  CAS  PubMed  Google Scholar 

  19. Cossarizza A, Baccarani-Contri M, Kalashnikova G, Franceschi C (1993) A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem Biophys Res Commun 197:40–45

    Article  CAS  PubMed  Google Scholar 

  20. Wang D, Wong HK, Feng YB, Zhang ZJ (2013) Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells. Cell Mol Neurobiol 33:521–529. doi:10.1007/s10571-013-9914-y

    Article  CAS  PubMed  Google Scholar 

  21. Hibasami H, Iwase H, Yoshioka K, Takahashi H (2006) Glycyrrhetic acid (a metabolic substance and aglycon of glycyrrhizin) induces apoptosis in human hepatoma, promyelotic leukemia and stomach cancer cells. Int J Mol Med 17:215–219

    CAS  PubMed  Google Scholar 

  22. El-Najjar N, Chatila M, Moukadem H, Vuorela H, Ocker M, Gandesiri M, Schneider-Stock R, Gali-Muhtasib H (2010) Reactive oxygen species mediate thymoquinone-induced apoptosis and activate ERK and JNK signaling. Apoptosis 15:183–195. doi:10.1007/s10495-009-0421-z

    Article  CAS  PubMed  Google Scholar 

  23. Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48:749–762

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Lee CS, Kim YJ, Lee MS, Han ES, Lee SJ (2008) 18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci 83:481–489

    Article  CAS  PubMed  Google Scholar 

  25. Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117:333–340

    Article  CAS  PubMed  Google Scholar 

  26. Festa M, Capasso A, D’Acunto CW, Masullo M, Rossi AG, Pizza C, Piacente S (2011) Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. J Nat Prod 74:2505–2513. doi:10.1021/np200390x

    Article  CAS  PubMed  Google Scholar 

  27. Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, Gonzalez L, Nakayama K, Nakayama KI, Fernandez-Sousa JM, Munoz A, Sanchez-Puelles JM (2002) Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene 21:7533–7544. doi:10.1038/sj.onc.1205972

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Z, Teruya K, Eto H, Shirahata S (2011) Fucoidan extract induces apoptosis in MCF-7 cells via a mechanism involving the ROS-dependent JNK activation and mitochondria-mediated pathways. PLoS One 6:e27441. doi:10.1371/journal.pone.0027441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Pitt GS (2007) Calmodulin and CaMKII as molecular switches for cardiac ion channels. Cardiovasc Res 73:641–647

    Article  CAS  PubMed  Google Scholar 

  30. Hinshaw DB, Miller MT, Omann GM, Beals TF, Hyslop PA (1993) A cellular model of oxidant-mediated neuronal injury. Brain Res 615:13–26

    Article  CAS  PubMed  Google Scholar 

  31. Pereira CF, Oliveira CR (2000) Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis. Neurosci Res 37:227–236

    Article  CAS  PubMed  Google Scholar 

  32. Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME (2008) A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Timmins JM, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, Backs T, Bassel-Duby R, Olson EN, Anderson ME, Tabas I (2009) Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J Clin Invest 119:2925–2941. doi:10.1172/JCI38857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Storling J, Zaitsev SV, Kapelioukh IL, Karlsen AE, Billestrup N, Berggren PO, Mandrup-Poulsen T (2005) Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells. Endocrinology 146:3026–3036

    Article  CAS  PubMed  Google Scholar 

  35. Kuang P, Zhao W, Su W, Zhang Z, Zhang L, Liu J, Ren G, Yin Z, Wang X (2013) 18beta-Glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell-mediated immunosuppression in mice. Int J Cancer 132:1831–1841. doi:10.1002/ijc.27852

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by General Research Fund (GRF) of Research Grant Council of HKSAR (Project Reference No.: 785813) and HKU intramural Seed Funding Program for Basic Research (Project Reference No.: 201210159051).

Conflict of interest

The authors have declared that there is no conflict of interest.

Author information

Authors and Affiliations

  1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China

    Di Wang, Hei-Kiu Wong, Yi-Bin Feng & Zhang-Jin Zhang

  2. College of Life Science, Jilin University, Changchun, 130012, Jilin, China

    Di Wang

Authors
  1. Di Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hei-Kiu Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi-Bin Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhang-Jin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhang-Jin Zhang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 871 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, D., Wong, HK., Feng, YB. et al. 18beta-Glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol 116, 221–230 (2014). https://doi.org/10.1007/s11060-013-1292-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-013-1292-2

Keywords

Search

Navigation