Spermidine/spermine N1-acetyltranferase modulation by novel folate cycle inhibitors in cisplatin-sensitive and -resistant human ovarian cancer cell lines.
OBJECTIVE
Polyamines have been shown to play a role in the growth and survival of several solid tumors, including ovarian cancer. Intracellular polyamine depletion by the inhibition of biosynthesis enzymes or by the induction of the catabolic pathway leads to antiproliferative effects in many different tumor cell lines. Recent studies showed that the thymidylate synthase inhibitor 5-fluorouracil (5-FU) affects polyamine metabolism in colon carcinoma cells through the induction of the key catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT).


METHODS
We therefore examined whether combinations of novel folate cycle inhibitors with quinoxaline structure and drugs that specifically target polyamine metabolism, such as diethylderivatives of norspermine (DENSPM) or spermine (BESpm), have synergistic effect in killing cisplatin-sensitive and drug-resistant daughter human ovarian cell lines.


RESULTS
Our results showed that simultaneous drug combination or quinoxaline pre-treatment synergistically increased SSAT expression, depleted polyamines, increased reactive oxygen species production, and produced synergistic tumor cell killing in both cell lines. Of note, this combined therapy increased the chemosensitivity of cisplatin-resistant cells and cross-resistant to the polyamine analogues. On the contrary, some pre-treatment regimens of Spm analogues were antagonistic.


CONCLUSIONS
These results show that SSAT plays an important role in novel folate cycle inhibitors effects and suggest that their combination with analogues has potential for development as therapy for ovarian carcinoma based on SSAT modulation.
Marverti
Gaetano
G
Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy. gaetano.marverti@unimore.it
Ligabue
Alessio
A
Guerrieri
Davide
D
Paglietti
Giuseppe
G
Piras
Sandra
S
Costi
Maria P
MP
Farina
Davide
D
Frassineti
Chiara
C
Monti
Maria G
MG
Moruzzi
Maria S
MS
D000123:Acetyltransferases / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011810:Quinoxalines / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D002945:Cisplatin; D005493:Folic Acid Antagonists; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine