title: Collateral sensitivity to novel thymidylate synthase inhibitors correlates with folate cycle enzymes impairment in cisplatin-resistant human ovarian cancer cells.
abstract: The cytotoxicity of two novel folate cycle inhibitors with quinoxalinic structure, 3-methyl-7-trifluoromethyl-2(R)-[3,4,5-trimethoxyanilino]-quinoxaline (453R) and 3-piperazinilmethyl-2[4(oxymethyl)-phenoxy]quinoxaline (311S), was tested against a panel of both cisplatin(cDDP)-sensitive and -resistant carcinoma cell lines. Interestingly, the cisplatin-resistant human ovarian line, C13 cells, exhibited collateral sensitivity towards the two compounds when compared to its sensitive parental 2008 cells. In this resistant line, which showed elevated expression of the folate cycle enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR), due to cisplatin-resistance phenotype, collateral sensitivity correlated with the greater reduction of enzyme expression. In addition, TS and DHFR expression of the other resistant lines, the human ovarian carcinoma A2780/CP cells and the human breast cancer MDA/CH cells, were decreased in accordance with the similar sensitivity or the low level of cross-resistance to these compounds in comparison to their respective parental lines. Noteworthy, unlike 5-fluorouracil, both drugs reduced the level of TS without inducing ternary complex formation with the co-substrate and the nucleotide analogue. Median effect analysis of the interactive effects of cisplatin with the two quinoxalines mainly showed additive or synergistic cell killing, depending on schedules of drug combinations. In particular, synergistic effects were more often obtained, even on the resistant cells, when cisplatin was added at the beginning of the treatment. These results indicate that, despite the possibility of other mechanisms being involved, inhibition of TS cycle enzymes plays an important role in the pharmacology of these compounds, which might also represent a useful component in drug treatment protocols against cDDP-resistant cells.
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy. marverti.gaetano@unimore.it
authors.forename: Gaetano
authors.initials: G
authors.lastname: Marverti
authors.forename: Alessio
authors.initials: A
authors.lastname: Ligabue
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paglietti
authors.forename: Paola
authors.initials: P
authors.lastname: Corona
authors.forename: Sandra
authors.initials: S
authors.lastname: Piras
authors.forename: Gabriella
authors.initials: G
authors.lastname: Vitale
authors.forename: Davide
authors.initials: D
authors.lastname: Guerrieri
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
authors.forename: Chiara
authors.initials: C
authors.lastname: Frassineti
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Moruzzi
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D010051:Ovarian Neoplasms; D011810:Quinoxalines / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D005493:Folic Acid Antagonists; D011810:Quinoxalines; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil