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.