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.

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…BESpm downregulated DHFR mRNA more than TS mRNA. BBR treatment reversed the resistance of the cells to cisplatin and BESpm (Marverti et al, 2013).…”

N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

“…We selected the non-tumorigenic Vero lineage as control cell line 53,54 . Administration of NCAO resulted in decreased cell viability and increased growth inhibition in a dose-and time-dependent manner, according to the trypan blue assay.…”

Anticancer activities and mechanisms of heat-clearing and detoxicating traditional Chinese herbal medicine

“…[19]. Considerable attention has been drawn to berberine since its prominent anticancer activity including tongue squamous cancer, esophageal cancer, hepatocelluar cancer, breast cancer, lung cancer, gastric cancer, ovarian cancer, renal cancer, nasopharyngeal cancer and Wilms’ tumor [20]. Berberine has been proved to be a heat-clearing and detoxifying compound which acts on diverse cancer cell types through various mechanisms.…”