Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013, 157(2):153-161 | DOI: 10.5507/bp.2013.031

The anticancer activity of alpha-tomatine against mammary adenocarcinoma in mice

Pavel Tomsika, Stanislav Micudab, Lenka Suchaa, Eva Cermakovac, Petr Subaa, Pavel Zivnyf, Yvona Mazurovae, Jiri Knizekd, Mohamed Nianga, Martina Rezacovaa
a Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
b Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove
c Computer Technology Centre, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove
d Department of Medical Biophysics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove
e Department of Histology and Embryology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove
f Institute for Clinical Biochemistry and Diagnostics, University Hospital in Hradec Kralove, Hradec Kralove

Aim: To evaluate the anticancer effect of alpha-tomatine (i.p.) either alone or in combination with doxorubicin (i.v.) in a mouse tumour model.

Methods: We studied the effect of repeated alpha-tomatine (0.1 - 9 mg/kg) and/or doxorubicin (2 mg/kg) on the growth and mitotic activity of the solid Ehrlich tumour in vivo, as well as on the survival of the tumour-bearing mice.

Results: Monotherapy with alpha-tomatine had a significant dose-dependent anticancer effect which peaked at 1 mg/kg. This was shown by both slowed tumour growth and reduced tumour cell proliferation. We also provide the first evidence that the combination alpha-tomatine (1 mg/kg) and doxorubicin (2 mg/kg) had a synergistic effect and significantly prolonged the survival of the mice. Neither alpha-tomatine nor doxorubicin influenced the infiltration of tumours with CD3+ lymphocytes; nor were we able to find an in vivo modulation of the key molecules of two regulatory pathways reported in vitro as the principal anti-cancer mechanisms of alpha-tomatine, i.e. iNOS and phosphorylated ERK2. However, alpha-tomatine still led to intracellular DNA inhibition and protein synthesis in Ehrlich tumour cells in a short-term culture ex vivo with IC50 values of 8.7 and 6.6 µM.

Conclusions: The results suggest that ΤΟΜ, especially in combination with doxorubicin, may be a promising agent for the treatment of malignant solid tumours. Despite growing knowledge of the mechanisms of ΤΟΜ action in cancer cells, most aspects remain unclear. Parallel organ toxicity, especially potential liver effects, requires careful attention when performing in vivo studies in the future.

Keywords: alpha-tomatine, doxorubicin, cancer, survival, Ehrlich tumour

Received: January 23, 2013; Accepted: April 17, 2013; Prepublished online: May 3, 2013; Published: June 21, 2013  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Tomsik, P., Micuda, S., Sucha, L., Cermakova, E., Suba, P., Zivny, P., ... Rezacova, M. (2013). The anticancer activity of alpha-tomatine against mammary adenocarcinoma in mice. Biomedical papers157(2), 153-161. doi: 10.5507/bp.2013.031
Download citation

References

  1. Friedman M. Tomato glycoalkaloids: Role in the plant and in the diet. J Agric Food Chem 2002;50:5751-80. Go to original source... Go to PubMed...
  2. Schmidt B, Ribnicky DM, Poulev A, Logendra S, Cefalu WT, Raskin I. A natural history of botanical therapeutics. Metabolism 2008;57:S3-9. Go to original source... Go to PubMed...
  3. Friedman M, Fitch TE, Yokoyama WE. Lowering of plasma LDL cholesterol in hamsters by the tomato glycoalkaloid tomatine. Food Chem Toxicol 2000;38:549-53. Go to original source... Go to PubMed...
  4. Thorne HV, Clarke GF, Skuce R. The inactivation of herpes simplex virus by some Solanaceae glycoalkaloids. Antiviral Res 1985;5:335-43. Go to original source... Go to PubMed...
  5. Morrow WJW, Yang YW, Sheikh NA. Immunobiology of the tomatine adjuvant. Vaccine 2004;22:2380-4. Go to original source... Go to PubMed...
  6. Friedman M, McQuistan T, Hendricks JD, Pereira C, Bailey GS. Protective effect of dietary tomatine against dibenzo[a,l]pyrene (DBP)-induced liver and stomach tumors in rainbow trout. Mol Nutr Food Res 2007;51:1485-91. Go to original source... Go to PubMed...
  7. Lee KR, Kozukue N, Han JS, Park JH, Chang EY, Baek EJ, Chang JS, Friedman M. Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. J Agric Food Chem 2004;19:2832-9. Go to original source...
  8. Friedman M, Levin CE. Tomatine-containing green tomato extracts inhibit growth of human breast, colon, liver, and stomach cancer cells. J Agric Food Chem 2009;57:5727-33. Go to original source... Go to PubMed...
  9. Chiu FL, Lin JK. Tomatidine inhibits iNOS and COX-2 through suppression of NF-kappaB and JNK pathways in LPS-stimulated mouse macrophages. FEBS Lett 2008;582:2407-12. Go to original source... Go to PubMed...
  10. Shih YW, Shieh J M, Wu PF, Lee YC, Chen YZ, Chiang TA. α-Tomatine inactivates PI3K/Akt and ERK signaling pathways in human lung adenocarcinoma A549 cells: effect on metastasis. Food Chem Toxicol 2009;47:1985-95. Go to original source... Go to PubMed...
  11. Liao DW, Wang L, Zhang XG, Liu MQ. Expression and significance of PTEN/PI3K signal transduction-related proteins in non-small cell lung cancer. Chin J Canc 2006; 25:1238-42.
  12. Itoh Y, Nagase H. Matrix metalloproteinases in cancer. Essays Biochem 2002;38,21-36. Go to original source... Go to PubMed...
  13. Duffy MJ, Duggan C. The urokinase plasminogen activator system: A rich source of tumor markers for the individualised management of patients with cancer. Clin Biochem 2004;37:541-8. Go to original source... Go to PubMed...
  14. Lee ST, Wong PF, Cheah SC, Mustafa MR Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells.. PLoS ONE 2011;6:e18915. Go to original source... Go to PubMed...
  15. Shieh JM, Cheng TH, Shi MD, Wu PF, Chen Y, Ko SC, Shih YW. α-Tomatine suppresses invasion and migration of human non-small cell lung cancer NCI-H460 cells through inactivating FAK/PI3K/Akt signaling pathway and reducing binding activity of NF-κB. Cell Biochem Biophys 2011;60:297-310. Go to original source... Go to PubMed...
  16. Chao MW, Chen CH, Chang YL, Teng CM, Pan SL. α-Tomatine-Mediated Anti-Cancer Activity In Vitro and In Vivo through Cell Cycle- and Caspase-Independent Pathways. PLoS ONE 2012;9:e44093. Go to original source...
  17. Kudelova J, Seifrtova M, Sucha L, Tomsik P, Havelek R, Rezacova M. Alpha-tomatine activates cell cycle checkpoints in the absence of DNA damage in human leukemic MOLT-4 cells. J Appl Biomed 2013;11:93-103. Go to original source...
  18. Nishie K, Norred WP, Swain AP. Pharmacology and toxicology of chaconine and tomatine. Res Commun Chem Pathol Pharmacol 1975;12:657-68. Go to PubMed...
  19. Awara WM, El-Sisi AE, El-Sayad ME, Goda AE. The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of DOX? Pharmacol Res 2004;50:487-98. Go to original source... Go to PubMed...
  20. Klein HO, Toermer HJ, Christian E, Coerper C, Lennartz KJ, Akokan G. Experimental investigations on a sequential combination chemotherapy protocol. J Cancer Res Clin Oncol 1980;96:65-78. Go to original source... Go to PubMed...
  21. Mattern J, Kaufmann M, Wayss K, Volm M. Studies on the Drug Sensitivity of Short Term Cultivated Tumor Cell Suspensions. In: Dendy, PP,editor. Human Tumors in Short Term Culture, Academic Press, London (UK), New York (NY), San Francisco (CA); 1976. p 301.
  22. Tomsik P, Stoklasova A, Micuda S, Niang M, Suba P, Knizek J, Rezacova M. Evaluation of the antineoplastic activity of L-rhamnose in vitro. A comparison with 2-deoxyglucose. Acta Med (Hradec Kralove) 2008;51:113-9. Go to original source... Go to PubMed...
  23. Pessina A, Brambilla P, Mocarelli P. Surface antigen on Ehrlich ascites tumor cells. Biomedicine 1980;33:105-9. Go to PubMed...
  24. Segura JA, Barbero LG, Marquez J. Early tumor effect on splenic Th lymphocytes in mice. FEBS Lett 1997;414:1-6. Go to original source... Go to PubMed...
  25. Cespedes MV, Casanova I, Parreno M, Mangues R. Mouse models in oncogenesis and cancer therapy. Clin Transl Oncol 2006;8:318-29. Go to original source... Go to PubMed...
  26. Polin L, Corbett TH, Roberts BJ, Lawson AJ, Leopold III WR, White K, Kushner J, Hazeldine S, Moore R, Rake J, Horwitz JP. Transplantable Syngeneic Rodent Tumors. In: Teicher BA, editor. Tumor Models in Cancer Research, 2nd edn. Humana Press, Springer: New York (NY), Dordrecht (Netherlands), Heidelberg (Germany), London (UK); 2011. p 47 Go to original source...
  27. Haque E, Baral R. Neem (Azadirachta indica) leaf preparation induces prophylactic growth inhibition of murine Ehrlich carcinoma in Swiss and C57BL/6 mice by activation of NK cells and NK-T cells. Immunobiology 2006;211:721-31. Go to original source... Go to PubMed...
  28. Israel M, Idriss JM, Koseki Y, Khetarpal VK. Comparative effects of adriamycin and DNA-non-binding analogues on DNA, RNA, and protein synthesis in vitro. Cancer Chemother Pharmacol 1987;20:277-84. Go to original source... Go to PubMed...
  29. Schaefer A, Boldt J, Westendorf J, Steinheider G, Marquardt H. Inhibition of amino acid uptake and incorporation into proteins in Friend erythroleukemia cells by the anthracycline antitumor antibiotic aclacinomycin A. Biochem Pharmacol 1988;37: 1377-82. Go to original source... Go to PubMed...
  30. Ebbehoj E, Langkjer ST. Comparison between different parameters of cell viability. In vitro studies in a human cervix cancercell line. J Exp Clin Cancer Res 1995;14:95-101.
  31. Lavie Y, Harel-Orbital T, Gaffield W, Liscovitch M. Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human cancer cells. Anticancer Res 2001;21:1189-94. Go to PubMed...
  32. Keukens EA, de Vrije T; van den Boom C, de Waard P, Plasman HH, Thiel F, Chupin V, Jongen WM, de Kruijff B. Molecular basis of glycoalkaloid induced membrane disruption. Biochim Biophys Acta 1995;1240:216-28. Go to original source... Go to PubMed...
  33. Keukens EA, de Vrije T, Jansen LA, de Boer H, Janssen M, de Kroon AI, Jongen WM, de Kruijff B. Glycoalkaloids selectively permeabilize cholesterol containing biomembranes. Biochim Biophys Acta 1996;1279:243-50. Go to original source... Go to PubMed...
  34. Walker BW, Manhanke N, Stine KJ. Comparison of the interaction of tomatine with mixed monolayers containing phospholipid, egg sphingomyelin, and sterols. Biochim Biophys Acta 2008;1778:2244-57. Go to original source... Go to PubMed...
  35. Hartveit F. The growth of Ehrlich's ascites carcinoma in C3H mice and in mice of an unrelated closed colony. Splenomegaly following intraperitoneal transplantation. Br J Cancer 1966;20:825-30. Go to original source... Go to PubMed...
  36. Lala PK, Terrin M, Lind C, Kaizer L. Hemopoietic redistribution in tumor-bearing mice. Exp Hematol 1978;6:283-98. Go to PubMed...
  37. Rivenson A, Schnelle V, Moroson H, Madden R, Herp A. Variable response of spleen to ehrlich's tumor according to the physical form (ascitic or solid) of the tumor. Experientia 1981;37:195-7. Go to original source... Go to PubMed...
  38. Queiroz ML, Valadares MC, Bincoletto C, Dieamant GC. Ehrlich ascites tumor as a tool in the development of compounds with immunomodulatory properties. Immunopharmacol Immunotoxicol 2004;26:511-25. Go to original source... Go to PubMed...
  39. Theologides A, Pegelow CH. Liver weight changes during distant growth of transplanted tumor. Proc Soc Exp Biol Med 1970;134:1104-8. Go to original source... Go to PubMed...
  40. Friedman M, Henika PR, Mackey BE. Feeding of potato, tomato and eggplant alkaloids affects food consumption and body and liver weights in mice. J Nutr 1996;126:989-9. Go to original source... Go to PubMed...
  41. Dalvi RR. Comparative assessment of the effect of solanine administered orally and intraperitoneally on hepatic dysfunction in male rats. Jpn J Vet Sci (Nihon Juigaku Zasshi) 1985;47:657-9. Go to original source... Go to PubMed...
  42. Kathiriya A, Das K, Kumar EP, Mathai KB. Evaluation of antitumor and antioxidant activity of Oxalis Corniculata Linn. against ehrlich ascites carcinoma on mice. Iran J Cancer Prev 2010;3:157-65.
  43. Naveena, Bharath BK, Selvasubramanian. Antitumor activity of Aloe vera against Ehrlich ascitis carcinoma (EAC) in Swiss albino mice. Int J Pharm Bio Sci 2011;2:400-9. Go to original source...
  44. Wilson RW, Poley GH, de Eds F. Some pharmacologic and toxicologic properties of tomatine and its derivatives. Toxicol Appl Pharmacol 1961;3:39-48. Go to original source... Go to PubMed...
  45. Mimnaugh EG, Trush MA, Ginsburg E. The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes: Role of microsomal lipid peroxidation. Toxicol Appl Pharmacol 1981;61:313-25. Go to original source... Go to PubMed...