Methanol extract of the ethnopharmaceutical remedy Smilax spinosa exhibits anti-neoplastic activity

  • Authors:
    • Mareike Seelinger
    • Ruxandra Popescu
    • Benedikt Giessrigl
    • Kanokwan  Jarukamjorn
    • Christine  Unger
    • Bruno Wallnöfer
    • Monika Fritzer-Szekeres
    • Thomas  Szekeres
    • Rene Diaz
    • Walter Jäger
    • Richard Frisch
    • Brigitte Kopp
    • Georg Krupitza
  • View Affiliations

  • Published online on: June 29, 2012     https://doi.org/10.3892/ijo.2012.1538
  • Pages: 1164-1172
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Plants have been the source of several effective drugs for the treatment of cancer and over 60% of anticancer drugs originate from natural sources. Therefore, extracts of the rhizome of Smilax spinosa, an ethnomedicinal plant from Guatemala which is used for the treatment of inflammatory conditions, were investigated regarding their anti-neoplastic activities. By using several solvents the methanol extract was by far the most potent against HL60 cell proliferation (50% inhibition at 60 µg/ml). Furthermore, fractionation of this extract yielded fraction F2, which exhibited enforced pro-apoptotic activity, and activated CYP1A1. Proteins that are relevant for cell cycle progression and apoptosis, as well as proto-oncogenes were investigated by western blotting. This revealed that the methanol extract increased the levels of p21 and this may have caused cell cycle attenuation. The derivative fraction F2 induced apoptosis through the intrinsic pathway, which correlated with the inhibition of Stat3 phosphorylation and concomitant induction of caspase 9, then caspase 8 and caspase 3. In summary, the methanol extract and the derivative fraction F2 of S. spinosa showed anti-neoplastic effects in HL-60 cells and CYP1A1 activation in estrogen receptor-positive MCF-7 breast cancer cells but not in estrogen-negative MDA-MB231 breast cancer cells. Based on our data Smilax spinosa may be a promising source for novel anticancer agents.

References

1. 

Pecorino L: Molecular Biology of Cancer. 2nd edition. Oxford University Press; New York, NY: 2008

2. 

Stewart BW and Kleihues P: World Cancer Report. IARC Press; Lyon: 2003

3. 

Cragg GM and Newman DJ: Plants as a source of anti-cancer agents. J Ethnopharmacol. 100:72–79. 2005.PubMed/NCBI

4. 

Fabricant DS and Farnsworth NR: The value of plants used in traditional medicine for drug discovery. Environ Health Perspect. 109:69–75. 2001. View Article : Google Scholar : PubMed/NCBI

5. 

Rastogi RP and Dhawan BN: Research on medicinal plants at the Central Drug Research Institute, Lucknow (India). Indian J Med Res. 76:27–45. 1982.PubMed/NCBI

6. 

Cseke LJ: Natural products from plants. 2nd edition. CRC Press Taylor and Francis; Boca Raton, FL: 2006

7. 

Shoeb M: Anticancer agents from medicinal plants. Bangladesh J Pharmacol. 1:35–41. 2006.

8. 

Kundu JK and Surh YJ: Inflammation: gearing the journey to cancer. Mutat Res. 659:15–30. 2008. View Article : Google Scholar : PubMed/NCBI

9. 

Taylor L: The Healing Power of Rainforest Herbs: A Guide to Understanding and Using Herbal Medicinals. Square One Publishers; New York, NY: 2005

10. 

Caceres A, Cano O, Samayoa B and Aguilar L: Plants used in Guatemala for the treatment of gastrointestinal disorders. 1 Screening of 84 plants against enterobacteria. J Ethnopharmacol. 30:55–73. 1990. View Article : Google Scholar : PubMed/NCBI

11. 

Jiang J and Xu Q: Immunomodulatory activity of the aqueous extract from rhizome of Smilax glabra in the later phase of adjuvant-induced arthritis in rats. J Ethnopharmacol. 85:53–59. 2003. View Article : Google Scholar : PubMed/NCBI

12. 

Alam MI and Gomes A: Adjuvant effects and antiserum action potentiation by a (herbal) compound 2-hydroxy-4-methoxy benzoic acid isolated from the root extract of the Indian medicinal plant ‘sarsaparilla’ (Hemidesmus indicus R. Br.). Toxicon. 36:1423–1431. 1998.PubMed/NCBI

13. 

Navarro MC, Montilla MP, Cabo MM, Galisteo M, Cáceres A, Morales C and Berger I: Antibacterial, antiprotozoal and antioxidant activity of five plants used in Ibazal for infectious. Phytother Res. 17:325–329. 2003. View Article : Google Scholar : PubMed/NCBI

14. 

Arvigo R and Balick M: Rainforest Remedies. One Hundred Healing Herbs of Belize. 2nd edition. Lotus Press; Twin Lakes, WI: pp. 72–73. 1998

15. 

Gridling M, Stark N, Madlener S, Lackner A, Popescu R, Benedek B, Diaz R, Tut FM, Nha Vo TP, Huber D, et al: In vitro anti-cancer activity of two ethno-pharmacological healing plants from Guatemala Pluchea odorata and Phlebodium decumanum. Int J Oncol. 34:1117–1128. 2009.

16. 

Stark N, Gridling M, Madlener S, Bauer S, Lackner A, Popescu R, Diaz R, Tut FM, Vo TP, Vonach C, et al: A polar extract of the Maya healing plant Anthurium schlechtendalii (Aracea) exhibits strong in vitro anticancer activity. Int J Mol Med. 24:513–521. 2009.PubMed/NCBI

17. 

Strasser S, Maier S, Leisser C, Saiko P, Madlener S, Bader Y, Bernhaus A, Gueorguieva M, Richter S, R. Mader RM, et al: 5-FdUrd-araC heterodinucleoside re-establishes sensitivity in 5-FdUrd- and AraC- resistant MCF-7 breast cancer cells overexpressing ErbB2. Differentiation. 74:488–498. 2006. View Article : Google Scholar : PubMed/NCBI

18. 

Maier S, Strasser S, Saiko P, Leisser C, Sasgary S, Grusch M, Madlener S, Bader Y, Hartmann J, Schott H, et al: Analysis of mechanisms contributing to AraC-mediated chemoresistance and re-establishment of drug sensitivity by the novel heterodinucleoside phosphate 5-FdUrd-araC. Apoptosis. 11:427–440. 2006. View Article : Google Scholar : PubMed/NCBI

19. 

Hüttenbrenner S, Maier S, Leisser C, Polgar D, Strasser S, Grusch M and Krupitza G: The evolution of cell death programs as prerequisites of multicellularity. Rev Mutat Res. 543:235–249. 2003.PubMed/NCBI

20. 

Grusch M, Fritzer-Szekeres M, Fuhrmann G, Rosenberger G, Luxbacher C, Elford HL, Smid K, Peters GJ, Szekeres T and Krupitza G: Activation of caspases and induction of apoptosis by amidox and didox. Exp Haematol. 29:623–632. 2001. View Article : Google Scholar : PubMed/NCBI

21. 

Madlener S, Rosner M, Krieger S, Giessrigl B, Gridling M, Vo TP, Leisser C, Lackner A, Raab I, Grusch M, et al: Short 42 degrees C heat shock induces phosphorylation and degradation of Cdc25A which depends on p38MAPK, Chk2 and 14.3.3. Hum Mol Genet. 18:1990–2000. 2009. View Article : Google Scholar : PubMed/NCBI

22. 

Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI

23. 

Blomberg I and Hoffmann I: Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases. Mol Cell Biol. 19:6183–6194. 1999.PubMed/NCBI

24. 

Kiyokawa H and Ray D: In vivo roles of CDC25 phosphatases: biological insight into the anti-cancer therapeutic targets. Anticancer Agents Med Chem. 8:832–836. 2008. View Article : Google Scholar : PubMed/NCBI

25. 

Meeran SM and Katiyar SK: Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci. 13:2191–2202. 2008. View Article : Google Scholar : PubMed/NCBI

26. 

Wolf D and Rotter V: Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc Natl Acad Sci USA. 82:790–794. 1985. View Article : Google Scholar : PubMed/NCBI

27. 

Abukhdeir AM and Park BH: P21 and p27: roles in carcinogenesis and drug resistanc. Expert Rev Mol Med. 10:e192008. View Article : Google Scholar : PubMed/NCBI

28. 

Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN and Golub TR: Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Sci USA. 97:3260–3265. 2000. View Article : Google Scholar : PubMed/NCBI

29. 

Chang C, Zhu YQ, Mei JJ, Liu SQ and Luo J: Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells. J Exp Clin Cancer Res. 29:145–154. 2010. View Article : Google Scholar : PubMed/NCBI

30. 

Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M and Bonner WM: A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 10:886–895. 2000. View Article : Google Scholar : PubMed/NCBI

31. 

Piperno G, LeDizet M and Chang J: Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol. 104:289–302. 1987. View Article : Google Scholar : PubMed/NCBI

32. 

Jackson CB and Giraud AS: Stat3 as a prognostic marker in human gastric cancer. J Gastroenterol Hepatol. 24:505–507. 2009. View Article : Google Scholar : PubMed/NCBI

33. 

Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, Kawashima T, Nanakin A, Sawabu T, Uenoyama Y, et al: Stat3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene. 23:4921–4929. 2004. View Article : Google Scholar : PubMed/NCBI

34. 

Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, et al: Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 12:11–19. 2006. View Article : Google Scholar : PubMed/NCBI

35. 

Deng JY, Sun D, Liu XY, Pan Y and Liang H: Stat-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol. 16:5380–5387. 2010. View Article : Google Scholar : PubMed/NCBI

36. 

Zhao M, Jiang B and Gao FH: Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem. 18:4012–4018. 2011. View Article : Google Scholar : PubMed/NCBI

37. 

Gündogdu MS, Liu H, Metzdorf D, Hildebrand D, Aigner M, Aktories K, Heeg K and Kubatzky KF: The haematopoietic GTPase RhoH modulates IL3 signalling through regulation of Stat activity and IL3 receptor expression. Mol Cancer. 9:225–238. 2010.PubMed/NCBI

38. 

Jinawath N, Vasoontara C, Jinawath A, Fang X, Zhao K, Yap KL, Guo T, Lee CS, Wang W, Balgley BM, et al: Oncoproteomic analysis reveals co-upregulation of RELA and Stat5 in carboplatin resistant ovarian carcinoma. PLoS One. 5:e111982010. View Article : Google Scholar : PubMed/NCBI

39. 

Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J and Dalla-Favera R: Non-transcriptional control of DNA replication by c-Myc. Nature. 448:445–451. 2007. View Article : Google Scholar : PubMed/NCBI

40. 

Wang H, Birkenbach M and Hart J: Expression of Jun family members in human colorectal adenocarcinoma. Carcinogenesis. 21:1313–1317. 2000. View Article : Google Scholar : PubMed/NCBI

41. 

Mathiasen DP, Egebjerg C, Andersen SH, Rafn B, Puustinen P, Khanna A, Daugaard M, Valo E, Tuomela S, Bøttzauw T, et al: Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation. Oncogene. 31:390–401. 2012. View Article : Google Scholar : PubMed/NCBI

42. 

Ivanova A, Mikhova B, Klaiber I, Dinchev D and Kostova I: Steroidal saponins from Smilax excelsa rhizomes. Nat Prod Res. 23:916–924. 2009. View Article : Google Scholar : PubMed/NCBI

43. 

Doyle BJ, Frasor J, Bellows LE, Locklear TD, Perez A, Gomez-Laurito J and Mahady GB: Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms. Menopause. 16:748–755. 2009. View Article : Google Scholar : PubMed/NCBI

44. 

Yu Z, Hu D and Li Y: Effects of zearalenone on mRNA expression and activity of cytochrome P450 1A1 and 1B1 in MCF-7 cells. Ecotoxicol Environ Saf. 58:187–193. 2004. View Article : Google Scholar : PubMed/NCBI

45. 

Sergentanis TN and Economopoulos KP: Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 122:459–469. 2010. View Article : Google Scholar : PubMed/NCBI

46. 

Sergentanis TN and Economopoulos KP: Erratum to: Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 131:10832012. View Article : Google Scholar : PubMed/NCBI

47. 

Kozak W, Mayfield KP, Kozak A and Kluger MJ: Proadifen (SKF-525A), an inhibitor of cytochrome P-450, augments LPS-induced fever and exacerbates prostaglandin-E2 levels in the rat. J Therm Biol. 25:45–50. 2000. View Article : Google Scholar

48. 

Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS and Liao JK: Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circ Res. 90:1020–1027. 2002. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2012
Volume 41 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Seelinger, M., Popescu, R., Giessrigl, B., Jarukamjorn, K., Unger, C., Wallnöfer, B. ... Krupitza, G. (2012). Methanol extract of the ethnopharmaceutical remedy Smilax spinosa exhibits anti-neoplastic activity. International Journal of Oncology, 41, 1164-1172. https://doi.org/10.3892/ijo.2012.1538
MLA
Seelinger, M., Popescu, R., Giessrigl, B., Jarukamjorn, K., Unger, C., Wallnöfer, B., Fritzer-Szekeres, M., Szekeres, T., Diaz, R., Jäger, W., Frisch, R., Kopp, B., Krupitza, G."Methanol extract of the ethnopharmaceutical remedy Smilax spinosa exhibits anti-neoplastic activity". International Journal of Oncology 41.3 (2012): 1164-1172.
Chicago
Seelinger, M., Popescu, R., Giessrigl, B., Jarukamjorn, K., Unger, C., Wallnöfer, B., Fritzer-Szekeres, M., Szekeres, T., Diaz, R., Jäger, W., Frisch, R., Kopp, B., Krupitza, G."Methanol extract of the ethnopharmaceutical remedy Smilax spinosa exhibits anti-neoplastic activity". International Journal of Oncology 41, no. 3 (2012): 1164-1172. https://doi.org/10.3892/ijo.2012.1538