Cytotoxic of Ganoderma lucidum in Colon Cancer through Cyclooxygenase 2 (COX-2) as Its Molecular Target

Agustina Setiawati

Abstract


Many studies were designed explore chemopreventive activity of natural products on colon cancer especially addressing COX-2 as molecular target. Another promising source of natural product that potentially exhibit anticancer activity on colon cancer is Ganoderma lucidum. This study assessed selectivity of cytotoxic effect of G. lucidum extract on WiDr to Vero cells and investigated molecular mechanism on COX-2. G. lucidum ex-tract was prepared by reflux extraction method; in vitro anticancer was assayed by MTT method on WiDr and Vero cell line. This study applied apoptosis induction assay to observe cell death mechanism using double staining method; further COX-2 expression was stained by immunocytochemistry method. G. lucidum extract has cytotoxic effect on WiDr cells with IC50 135 µg/mL. However, the cytotoxic effect had low selectivity to-wards Vero cells with Selectivity Index (SI) 3.66. The extract induced apoptosis and suppressed COX-2 ex-pression in WiDr cells. G. lucidum extract was potential to be developed as anticancer agent towards colon cancer.


Keywords


Ganoderma lucidum, selectivity, colon cancer, COX-2

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References


Torre LA, Bray F, Siegel RL et al. (2015) Global Cancer Statistics. CA: Cancer Journal for Clinicians 65: 87- 107. doi: 10.3322/caac.20107.

World Health Organization (2013) Latest world cancer statistics Global cancer burden rises to 14.1 million new cases in 2012: Marked increase in breast cancers must be addressed. https://www.iarc.fr/. Accessed: March 2015.

Kimman M, Norman R, Jan S et al. (2012) The Burden of cancer in member countries of the association of South-east Asian Nations (ASEAN). Asian Pacific Journal of Cancer Prevention 13 (2): 411-420.

Jemal A, Center MM, DeSantis C, Ward EM (2010) Global pattern of cancer incidence and mortality rates and trends. Cancer Epidemiology, Biomarkers and Pre-vention 9 (8): 1893- 1907. doi: 10.1158/1055-9965.EPI-10-0437.

Labianca R, Nordinger B, Beretta GD et al. (2010) Prima-ry colon cancer: ESMO clinical practical guidelines for diagnosis, adjuvant treatment and follow-up. Annals of Oncology 21 (Supplement_5): v70-v77. doi: 10.1093/annonc/mdq168.

Association of Coloproctology of Great Britain and Ire-land (2007) Guideline for the Management of Colorectal Cancer. London. 3rd Edition. http://www.uhb.nhs.uk/. Accessed: April 2015.

American Cancer Society. Colon Cancer: Facts and Fig-ure 2014-2016. https://www.cancer.org/ Accessed: April 2015.

Jiang Y, Zhang C, Chen K et al. (2014) The clinical signif-icance of DC-SIGN and DC-SIGNR, which are Novel markers expressed in human colon cancer. PLoS ONE. 9 (12): e114748. doi: 10.1371/journal.pone.0114748.

Wang XW, Zhang YJ (2014) Targeting mTOR network in colorectal cancer therapy. World Journal of Gastroenter-ol-

ogy 20 (15): 4178- 4188. doi: 10.3748/wjg.v20.i15.4178.

Mishra J, Dromund J, Quazi SH et al. (2013) Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Critical Re-views in Oncology/Hematology 86 (3): 232-250. doi: 10.1016/j.critrevonc.2012.09.014.

Dixon DA, Blanco FF, Bruno A, Patrignani P (2013) Mechanistic Aspects of COX-2 Expression in Colorectal Neoplasia. In: Chan AT, Detering E (eds) Prospect. Chemoprevention Color. Neoplasia. Berlin, Springer, pp 7–37. doi: 10.1007/978-3-642-30331-9_2.

Qi J, Dong Z, Liu J, Zhang JT (2014) EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and β-catenin activation. Oncogene 33 (32): 4156–4163. doi: 10.1038/onc.2013.397.

Roelofs HMJ, Te Morsche RHM, van Heumen BWH et al. (2014) Over-expression of COX-2 mRNA in colorectal cancer. BMC Gastroenterology 14 (1): 1- 6. doi: 10.1186/1471-230X-14-1.

Park J, Conteas CN (2010) Anti-carcinogenic properties of curcumin on colorectal cancer. World Journal of Gas-trointestinal Oncology 2 (4): 169-176. doi: 10.4251/wjgo.v2.i4.

Sobolewski C, Cerella C, Dicato M et al. (2010) The Role of Cyclooxygenase-2 in cell proliferation and cell death in human malignancies. International Journal of Cell Biolo-gy 2010 (2010): 1-21. doi: 10.1155/2010/215158.

Nakanishi M, Rosenberg DW (2013) Multifaceted roles of PGE2 in inflammation and cancer. Seminars in Immuno-pathology 35 (2): 123–137. doi: 10.1007/s00281-012-0342-8.

Li HJ, Reinhardt F, Herschman HR, Weinberg RA (2012)

Cancer-stimulated mesenchymal stem cells create a carci-noma stem-cell niche via Prostaglandin E2 signaling. Can-cer Discovery 2 (9): 840- 855. doi: 10.1158/2159-8290.CD-12-0101.

Ghosh N, Chaki R, Mandal V et al. (2011) COX-2 as a target for cancer chemotherapy. Pharmacological Reports. 62: 233-244.

Rahman M, Selvarajan K, Hasan MR et al. (2012) Inhibi-tion of COX-2 in colon cancer modulate tumor growth and MDR-1 expression to enhance tumor regression in therapy-refractory cancers in vivo. Neoplasia 14 (7): 624-633.

Kodela R, Chattopadhyay M, Goswami S et al. (2013) Positional isomers of Aspirin are equally potent in inhibit-ing colon cancer cell growth: Differences in mode of cy-clooxygenase inhibition. The Journal of Pharmacology and Experimental Therapeutics 345 (1): 85–94. doi: 10.1124/jpet.112.201970.

Makar KW, Poole EM, Resler AJ et al. (2013) COX-1

(PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancer in two independent populations. Cancer Causes and Control 24 (12): 2059–2075. doi: 0.1007/s10552-013-0282-1.

Kuno T, Tsukamoto T, Hara A, Tanaka T (2012) Cancer chemoprevention through the induction of apoptosis by natural compounds. Journal of Biophysical Chemistry 3 (2): 156- 173. doi: 10.4236/jbpc.2012.32018.

Rosas C, Sinning M, Ferreira A et al. (2014) Celecoxib decreases growth and angiogenesis and promotes apopto-sis in a tumor cell line resistant to chemotherapy. Biologi-cal Research 4 (1): 27. doi: 10.1186/0717-6287-47-2.

Jaganathan SK, Vellayappan MV, Narasimhan G, Su-priyanto E (2014) Role of pomegranate and citrus fruit juices in colon cancer prevention. World Journal of Gas-troenterology 20 (16): 4618-4625. doi: 10.3748/wjg.v20.i16.4618.

Amado NG, Predes D, Moreno MM et al. (2014) Flavo-noids and Wnt/β-Catenin signaling: Potential role in col-orectal cancer therapies. International Journal of Molecu-lar Science 15: 12094- 12106. doi: 10.3390/ijms150712094.

Nassar ZD, Aisha AF, Idris N et al. (2012) Koetjapic acid, a natural triterpenenoids, induces apoptosis in colon can-cer cells. Oncology Reports 27: 727- 733. doi: 10.3892/or.2011.1569.

Patel VB, Misra S, Patel BB, Majumdar APN (2010) Col-orectal cancer: Chemopreventive role of curcumin and resveratrol. Nutrition and Cancer 62 (7): 958-967. doi: 10.1080/01635581.2010.510259.

Galor SW, Yuen J, Buswell JA, Benzie IFF (2011) Ganoderma lucidum (Lingzhi or Reishi), a medicinal mushroom in herbal medicine: Biomolecular and clinical aspects 2nd edition. Florida, CRC Press/Taylor and Francis.

Arroyo IJ, Acevedo RR, Perez AA et al. (2013) Anti-tumor effects of Ganoderma ludicum (Reishi) in inflam-matory breast cancer in in vivo and in vitro models. PLoS One 8 (2): e57431. doi: 10.1371/journal.pone.0057431.

Zhao H, Zhang Q, Zhao L et al. (2012) Spore powder of Ganoderma lucidum improves cancer-related fatigue in breast cancer patients undergoing endocrine therapy: a pi-lot clinical trial. Evidence-Based Complementary and Al-ternative Medicine. doi: 10.1155/2012/809614

Dai L, Sun W (2014) Ganoderma lucidum inhibits prolif-eration of human ovarian cancer cells by suppressing VEGF expression and up-regulating the expression of connexin 43. BMC Complementary and Alternative Med-icine 14: 434. 14:434. doi: 10.1186/1472-6882-14-434.

Jang KJ, Han MH, Lee BH et al. (2010) Induction of apop-

tosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. Journal of Acupuncture and Merid-

ian Studies 3 (1): 24-31. doi: 10.1016/S2005-2901(10)60004-0.

Cao LZ, Lin ZB (2003) Regulatory effect of Ganoderma lucidum polysaccharides on cytotoxic T-lymphocytes in-duced by dendritic cells in vitro. Acta Pharmacologica Sinica 24 (4): 312-326.

Weng CJ, Chau CF, Yen GC et al. (2009) Inhibitory ef-fects of Ganoderma lucidum on tumorigenesis and metas-tasis of human hepatoma cells in cells and animal models. Journal of Agricultural and Food Chemistry 57 (11): 5049–5057. doi: 10.1021/jf900828k.

Kao CHJ, Jesuthasan AC, Bishop KS et al. (2013) Anti-cancer activities of Ganoderma lucidum: active ingredi-ents and pathways. Functional Food in Health and Dis-ease 3 (2): 48-65.

Calvino E, Pajuelo L, Casas OE et al. (2011) Cytotoxic Action of Ganoderma lucidum on Interleukin-3 Depend-ent Lymphoma DA-1 cells: Involvement of apoptosis pro-tein. Phytotherapy Research 25 (1): 25-32. doi: 10.1002/ptr.3202.

Wu GS, Guo JJ, Bao JL et al. (2013) Anti-cancer proper-ties of triterpenoids isolated from Ganoderma lucidum - a review. Expert Opinion on Investigational Drugs 22 (8): 981-92. doi: 10.1517/13543784.2013.805202.

Montemayor MM, Acevedo RR, Franqui EO et al. (2011) Ganoderma lucidum (Reishi) inhibits cancer cell growth and expression of key molecules in inflammatory breast cancer. Nutrition and Cancer 63 (7): 1085-1094. doi: 10.1080/01635581.2011.601845.

Jiang J, Slivova V, Harvey K et al. (2004) Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-κB signaling. Nutrition and Cancer 49 (2): 209- 216. doi: 10.1207/s15327914nc4902_13.

Thyagarajan A, Jedinak A, Nguyen H et al. (2010) Triter-penes from Ganoderma lucidum induce autophagy in co-lon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK). Nutrition and Cancer 62 (5): 630-640. doi: 10.1080/01635580903532390.

Hong KJ, Dunn DM, Shen CL, Pence BC (2004) Effects of Ganoderma lucidum on apoptotic and anti-inflammatory function in HT-29 human colonic carcino-ma cells. Phytotherapy Research 18 (9): 768–770. doi: 10.1002/ptr.1495.

Valadan S, Ahmadi R, Sadri M, Mahdavi E (2014) Anti-proliferative effects of Ganoderma lucidum in cell culture on Vero cells. In proceedings of International Conference on Chemical, Environment and Biological Sciences (CEBS – 2014): 17- 18 September 2014; Kuala Lumpur. Edited by Rahman A, Ahmadi R.

Moustafa SMA, Menshawi BM, Wassel GM et al. (2014) Screening of some plants in egypt for their cytotoxicity against four human cancer cell lines. International Jour-nal of PharmTech Research 6 (3): 1074-1084.

Irungu BN, Adipo N, Orwa JA et al. (2015) Antiplasmo-dial and cytotoxic activities of the constituents of Turraea robusta and Turraea nilotica. Journal of Ethnopharma-cology 174: 419-425. doi: 10.1016/j.jep.2015.08.039.

Setiawati A (2016) Celecoxib, A COX-2 selective inhibi-tor, induces cell cycle arrest at the G2 / M phase in hela cervical cancer cells. Asian Pacific Journal of Cancer Pre-vention 17 (4): 1655–1659.

Calderón-arancibia J, Espinosa-bustos C, Cañete-molina Á et al. (2015) Synthesis and pharmacophore modelling of 2,6,9-Trisubstituted Purine derivatives and their poten-tial role as apoptosis-inducing agents in cancer cell lines. Molecules 20 (4): 6808-6826. doi: 10.3390/molecules20046808.

Setiawati A, Immanuel H, Utami MT (2016) The Inhibi-tion of Typhonium flagelliforme Lodd. Blume leaf extract on COX-2 expression of WiDr colon cancer cells. Asian Pacific Journal of Tropical Biomedicine 6 (3): 251–255. doi: 10.1016/j.apjtb.2015.12.012.

U.S. Department of Health and Human Services - Food and Drug Administration (2016) Biological evaluation of medical devices - Part 5: Tests for cytotoxicity: in vitro methods.3: 42. https://www.fda.gov/. Accessed: April 2017.

Menezes C, Valerio E, Dias E (2013) The Kidney Vero-E6 Cell Line: A Suitable Model to Study the Toxicity of Mi-crocystins. New Insights into Toxic Drug Test. doi: 10.5772/54463

Awang N, Aziz ZA, Kamaludin NF, Chan KM (2014) Cytotoxicity and mode of cell death induced by Tri-phenyltin (IV) compounds in vitro. OnLine Journal of Biological Sciences 14 (2): 84-93. doi: 10.3844/ojbsci.2014.84.93.

Machana S, Weerapreeyakul N, Barusrux S et al. (2011) Cytotoxic and apoptotic effects of six herbal plants against the human hepatocarcinoma (HepG2) cell line. Chinese Medicine 6 (1): 39. doi: 10.1186/1749-8546-6-39.

Dixon DA, Blanco FF, Bruno A, Patrignani P (2013) Mechanistic aspects of COX-2 expression in colorectal neoplasia. Recent Results in Cancer Research 191: 7-37. doi: 10.1007/978-3-642-30331-9_2.




DOI: http://dx.doi.org/10.11594/jtls.07.02.14

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