Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Distamycin A interactions with Dickerson and Poly[d(AT)6] oligonucleotides show a different thermodynamic with respect to NAX002. The bulkier distamycin A analogue shows a non optimal binding to DNA due to its additional pyrrolamidine group. Cellular assays performed on cDDP-sensitive and -resistant cells showed that these compounds, distamycin A in particular, affect the expression of folate cycle enzymes even at cellular level. The optimal interaction of distamycin A with DNA may account for the down-regulation of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and the up-regulation of spermidine/spermine N1-acetyltransferase (SSAT) caused by this compound. These effects seem differently modulated by the cDDP-resistance phenotype. On the contrary, NAX002 which presents a lower affinity to DNA and slightly affected these enzymes, showed a synergic inhibition profile in combination with cDDP. In addition, their combination with cDDP or polyamine analogues increased cell sensitivity to the drugs suggesting that these interactions may have potential for development in the treatment of ovarian carcinoma.

Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells / Marverti, Gaetano; Guaitoli, Giambattista; Ligabue, Alessio; Frassineti, Chiara; Monti, Maria Giuseppina; P., Lombardi; Costi, Maria Paola. - In: AMINO ACIDS. - ISSN 1438-2199. - STAMPA. - 42(2-3):(2012), pp. 641-653. [10.1007/s00726-011-1039-3]

Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells.

MARVERTI, Gaetano;GUAITOLI, GIAMBATTISTA;LIGABUE, Alessio;FRASSINETI, Chiara;MONTI, Maria Giuseppina;COSTI, Maria Paola
2012-01-01

Abstract

Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Distamycin A interactions with Dickerson and Poly[d(AT)6] oligonucleotides show a different thermodynamic with respect to NAX002. The bulkier distamycin A analogue shows a non optimal binding to DNA due to its additional pyrrolamidine group. Cellular assays performed on cDDP-sensitive and -resistant cells showed that these compounds, distamycin A in particular, affect the expression of folate cycle enzymes even at cellular level. The optimal interaction of distamycin A with DNA may account for the down-regulation of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and the up-regulation of spermidine/spermine N1-acetyltransferase (SSAT) caused by this compound. These effects seem differently modulated by the cDDP-resistance phenotype. On the contrary, NAX002 which presents a lower affinity to DNA and slightly affected these enzymes, showed a synergic inhibition profile in combination with cDDP. In addition, their combination with cDDP or polyamine analogues increased cell sensitivity to the drugs suggesting that these interactions may have potential for development in the treatment of ovarian carcinoma.
42(2-3)
641
653
Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells / Marverti, Gaetano; Guaitoli, Giambattista; Ligabue, Alessio; Frassineti, Chiara; Monti, Maria Giuseppina; P., Lombardi; Costi, Maria Paola. - In: AMINO ACIDS. - ISSN 1438-2199. - STAMPA. - 42(2-3):(2012), pp. 641-653. [10.1007/s00726-011-1039-3]
Marverti, Gaetano; Guaitoli, Giambattista; Ligabue, Alessio; Frassineti, Chiara; Monti, Maria Giuseppina; P., Lombardi; Costi, Maria Paola
File in questo prodotto:
File Dimensione Formato  
fulltext-AminoAcids2011.pdf

Accesso riservato

Descrizione: Articolo principale
Tipologia: Versione dell'autore revisionata e accettata per la pubblicazione
Dimensione 421.49 kB
Formato Adobe PDF
421.49 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/708849
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 8
social impact