title: Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells.
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.
authors.affiliation: Department of Biomedical Sciences, Metabolic and Neuroscience, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, I-41125 Modena, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Marverti
authors.forename: Alessio
authors.initials: A
authors.lastname: Ligabue
authors.forename: Paolo
authors.initials: P
authors.lastname: Lombardi
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Monti
authors.forename: Chiara
authors.initials: C
authors.lastname: Frassineti
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D001599:Berberine / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011073:Polyamines / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000378:metabolism*; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D001599:Berberine; D002945:Cisplatin; D011073:Polyamines; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D000099228:Diamine N-Acetyltransferase