Cancer Chemopreventive Activity of Maslinic Acid: Suppression of COX-2 Expression and Inhibition of NF-κB and AP-1 Activation in Raji Cells

 

 Buy Article Permissions and Reprints

Abstract

Chronic inflammation is one of the predisposing factors for neoplastic transformation. Targeting inflammation through suppression of the pro-inflammatory pathway by dietary phytochemicals provides an important strategy for cancer prevention. Maslinic acid is a novel natural triterpenoid known to inhibit proliferation and induce apoptosis in some tumor cell lines. Although maslinic acid has cytotoxic and pro-apoptotic effects on cancer cells, the underlying mechanisms of its effects on the inflammatory pathway have yet to be elucidated. It has been reported that abnormal expression of pro-inflammatory enzyme cyclooxygenase-2 (COX-2) causes promotion of cellular proliferation, suppression of apoptosis, enhancement of angiogenesis and invasiveness. In the present study, the suppressive effect of maslinic acid on COX-2 expression and the binding activity of upstream transcription factors NF-κB and AP-1, which are known to regulate COX-2 transcriptional activation, were assessed using Raji cells. The anti-inflammatory action of maslinic acid was benchmarked against oleanolic acid and other standard drugs. Western blot analysis and electrophoretic mobility shift assay (EMSA) were employed to analyze COX-2 expression as well as NF-κB and AP-1 binding activity. Our results showed that maslinic acid suppresses COX-2 expression in a concentration-dependent manner. Likewise, the constitutive nuclear NF-κB (p65) activity as well as phorbol 12-myristate 13-acetate (PMA)- and sodium n-butyrate (SnB)-induced AP-1 binding activity in Raji cells were significantly reduced following treatment with maslinic acid. Since maslinic acid suppresses COX-2 expression in Raji cells at concentrations that also lowered the NF-κB (p65) and AP-1 binding activity, it is possible that the suppression of COX-2 by this natural triterpenoid might be achieved, at least in part, via the NF-κB and AP-1 signaling pathways.

References

• 1 Surh Y-J. Cancer chemoprevention with dietary phytochemicals.  Nat Rev Cancer. 2003;  3 768-780
  CrossrefPubMedGoogle Scholar
• 2 Bajaj Y P. Medicinal and aromatic plants. New York; Springer 1994: 69
  PubMedGoogle Scholar
• 3 Lim Y M, Wahab N A, Lajis N H, Ali A M. Chemopreventive property of phytosterols and maslinic acid in inhibiting the expression of EBV-early antigen in Raji cells.  Chem Biodivers. 2010;  7 1267-1275
  CrossrefPubMedGoogle Scholar
• 4 Reyes F J, Centelles J, Lupianez J A, Cascante M. (2α,3β)-2,3-Dihydroxyolean-12-en-28-oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells.  FEBS Lett. 2006;  580 6302-6310
  CrossrefPubMedGoogle Scholar
• 5 Liby K T, Yore M M, Sporn M B. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer.  Nat Rev Cancer. 2007;  7 357-368
  CrossrefPubMedGoogle Scholar
• 6 Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, Markova L, Urban M, Sarek J. Pharmacological activities of natural triterpenoids and their therapeutic implications.  Nat Prod Rep. 2006;  23 394-411
  CrossrefPubMedGoogle Scholar
• 7 Aggarwal B B, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer.  Biochem Pharmacol. 2006;  71 1397-1421
  CrossrefPubMedGoogle Scholar
• 8 Dannenberg A J, Subbaramaiah K. Targeting cyclooxygenase-2 in human neoplasia: rationale and promise.  Cancer Cell. 2003;  4 431-436
  CrossrefPubMedGoogle Scholar
• 9 Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T. Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxidase synthase 2.  Eur J Biochem. 1994;  221 889-897
  CrossrefPubMedGoogle Scholar
• 10 Dorai T, Aggarwal B B. Role of chemopreventive agents in cancer therapy.  Cancer Lett. 2004;  215 129-140
  CrossrefPubMedGoogle Scholar
• 11 Lim Y M. Anti-tumour promoting activity of selected malaysian vegetables and fruits, and identification of anti-tumour promoting and antioxidant compounds from Coleus tuberosus, Benth [dissertation]. Serdang; Universiti Putra Malaysia 2002
  PubMedGoogle Scholar
• 12 Chaturvedi M M, Mukhopadhyay A, Aggarwal B B. Assay for redox sensitive transcription factor.  Methods Enzymol. 2000;  319 585-602
  PubMedGoogle Scholar
• 13 Graf B A, Nazarenko D A, Borrello M A, Roberts L J, Morrow J D, Palis J, Phipps R P. Biophenotypic B/macrophage cells express COX-1 and up-regulate COX-2 expression and prostaglandin E(2) production in response to pro-inflammatory signals.  Eur J Immunol. 1999;  29 3793-3803
  CrossrefPubMedGoogle Scholar
• 14 Wun T, McKnight H, Tuscano J. Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma.  Leuk Res. 2004;  28 179-190
  CrossrefPubMedGoogle Scholar
• 15 Janakiram N B, Indranie C, Malisetty S V, Jagan P, Steele V E, Rao C V. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344 rats and modulation of COX-2 and apoptosis in human colon HT-29 cancer cells.  Pharm Res. 2008;  25 2151-2157
  CrossrefPubMedGoogle Scholar
• 16 Subbaramaiah K, Michaluart P, Sporn M B, Dannenberg A J. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells.  Cancer Res. 2000;  60 2399-2404
  PubMedGoogle Scholar
• 17 D'Acquisto F, Luvone T, Rombola L, Sautebin L, Di Rosa M, Carnuccio R. Involvement of NF-kB in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages.  FEBS Lett. 1997;  418 175-178
  CrossrefPubMedGoogle Scholar
• 18 McFarland E D, Davidson D M, Schauer S L, Duong J, Kieff E. NF-κB inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells.  Proc Natl Acad Sci. 2000;  97 6055-6060
  CrossrefPubMedGoogle Scholar
• 19 Bergera N, Bassatb H B, Kleinb B Y, Laskov R. Cytotoxicity of NF-kB inhibitors Bay 11-7085 and caffeic acid phenethyl ester to Ramos and other human B-lymphoma cell lines.  Exp Hematol. 2007;  35 1495-1509
  CrossrefPubMedGoogle Scholar
• 20 Eferl R, Wagner E F. AP-1: a double-edged sword in tumourigenesis.  Nat Rev Cancer. 2003;  3 859-868
  CrossrefPubMedGoogle Scholar
• 21 Sealy L, Chalky R. The effect of sodium butyrate on histone modification.  Cell. 1976;  14 115-121
  CrossrefPubMedGoogle Scholar
• 22 Reyes F Z, Palomares E R, Lupiáñez J M C. Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial pathway.  Cancer Lett. 2008;  273 44-54
  CrossrefPubMedGoogle Scholar
• 23 Montilla M, Agil A, Navarro M, Jimenez M, Granados A, Parra A, Cabo M M. Antioxidant activity of maslinic acid, a triterpene derivative obtained from Olea europaea.  Planta Med. 2003;  69 472-474
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Kim Y K, Yoon S K, Ryu S Y. Cytotoxic triterpenes from stem bark of Physocarpus intermedius.  Planta Med. 2000;  66 485-486
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Shaulian E, Karin M. AP-1 as a regulator of cell life and death.  Nat Cell Biol. 2002;  4 131-136
  CrossrefPubMedGoogle Scholar
• 26 Kundu J K, Surh Y-J. Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets.  Mutat Res. 2004;  555 65-80
  CrossrefPubMedGoogle Scholar
• 27 Schreck R, Rieber P, Baeurle P A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1.  EMBO J. 1991;  10 2247-2258
  PubMedGoogle Scholar
• 28 Liu J. Oleanolic acid and ursolic acid: research prospectives.  J Ethnopharmacol. 2005;  100 92-94
  CrossrefPubMedGoogle Scholar
• 29 Cipak L, Lubica G, Miadokova E, Novotny L, Rauko P. Dual activity of triterpenoids: apoptotic versus antidifferentiation affects.  Arch Toxicol. 2006;  80 429-435
  CrossrefPubMedGoogle Scholar
• 30 Yu X, Kensler T. Nrf2 as a target for cancer chemoprevention.  Mutat Res. 2005;  591 93-102
  PubMedGoogle Scholar

Dr. Lim Yang Mooi

Faculty of Engineering and Science
Universiti Tunku Abdul Rahman

Kuala Lumpur Campus, Jalan Genting Kelang

53300 Setapak

Kuala Lumpur

Malaysia

Phone: + 60 3 41 07 98 02 ext. 17 8

Fax: + 60 3 41 07 98 03

Email: ymlim@utar.edu.my

• Supplementary Material