Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells

  • Authors:
    • Gaetano Marverti
    • Alessio Ligabue
    • Paolo Lombardi
    • Stefania Ferrari
    • Maria Giuseppina Monti
    • Chiara Frassineti
    • Maria Paola Costi
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  • Published online on: July 31, 2013     https://doi.org/10.3892/ijo.2013.2045
  • Pages: 1269-1280
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Abstract

Berberine is a natural isoquinoline alkaloid with significant antitumor activity against many types of cancer cells, including ovarian tumors. This study investigated the molecular mechanisms by which berberine differently affects cell growth of cisplatin (cDDP)-sensitive and -resistant and polyamine analogue cross-resistant human ovarian cancer cells. The results show that berberine suppresses the growth of cDDP-resistant cells more than the sensitive counterparts, by interfering with the expression of folate cycle enzymes, dihydrofolate reductase (DHFR) and thymidylate synthase (TS). In addition, the impairment of the folate cycle also seems partly ascribable to a reduced accumulation of folate, a vitamin which plays an essential role in the biosynthesis of nucleic acids and amino acids. This effect was observed in both lines, but especially in the resistant cells, correlating again with the reduced tolerance to this isoquinoline alkaloid. The data also indicate that berberine inhibits cellular growth by affecting polyamine metabolism, in particular through the upregulation of the key catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT). In this regard, berberine is shown to stimulate the SSAT induction by the spermine analogue N1, N12 bisethylspermine (BESpm), which alone was also able to downregulate DHFR mRNA more than TS mRNA. We report that the sensitivity of resistant cells to cisplatin or to BESpm is reverted to the levels of sensitive cells by the co-treatment with berberine. These data confirm the intimate inter-relationships between folate cycle and polyamine pathways and suggest that this isoquinoline plant alkaloid could be a useful adjuvant therapeutic agent in the treatment of ovarian carcinoma.
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October 2013
Volume 43 Issue 4

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

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Spandidos Publications style
Marverti G, Ligabue A, Lombardi P, Ferrari S, Monti MG, Frassineti C and Costi MP: Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells. Int J Oncol 43: 1269-1280, 2013
APA
Marverti, G., Ligabue, A., Lombardi, P., Ferrari, S., Monti, M.G., Frassineti, C., & Costi, M.P. (2013). Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells. International Journal of Oncology, 43, 1269-1280. https://doi.org/10.3892/ijo.2013.2045
MLA
Marverti, G., Ligabue, A., Lombardi, P., Ferrari, S., Monti, M. G., Frassineti, C., Costi, M. P."Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells". International Journal of Oncology 43.4 (2013): 1269-1280.
Chicago
Marverti, G., Ligabue, A., Lombardi, P., Ferrari, S., Monti, M. G., Frassineti, C., Costi, M. P."Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells". International Journal of Oncology 43, no. 4 (2013): 1269-1280. https://doi.org/10.3892/ijo.2013.2045