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

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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. 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.

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Abbreviations

cDDP:

Cisplatin or cis-diamminedichloroplatinum

Put:

Putrescine

Spd:

Spermidine

Spm:

Spermine

SSAT:

Spermidine/spermine N1-acetyltransferase

BESpm: N1:

N12-bisethylspermine

DENSpm:

N1,N11-diethylnorspermine

ITC:

Isothermal titration calorimetry

DHFR:

Dihydrofolate reductase

TS:

Thymidylate synthase

5-FU:

5-fluorouracil

MTX:

Methotrexate

CH2FH4 :

5,10-methylenetetrahydrofolate

FH4 :

Tetrahydrofolate

DAPI:

4,6-diamidino-2-phenylindole dihydrochloride

Hoechst 33258:

Bisbenzimide H 33258

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Acknowledgments

This work is supported by EU LIGHTS (LIGands to interfere with Human Thymydilate Synthase) project of the 6th Framework Program, LSHCCT-2006-037852 and AIRC IG 10474 to M. P. Costi. This work is also supported by Associazione Angela Serra per la Ricerca sul Cancro, Azienda Ospedaliera Policlinico di Modena, Modena, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, University of Modena and Reggio Emilia, Via Campi 287, 41100, Modena, Italy

    Gaetano Marverti, Alessio Ligabue, Chiara Frassineti & Maria Giuseppina Monti

  2. Dipartimento di Scienze Farmaceutiche, University of Modena and Reggio Emilia, Via Campi 183, 41100, Modena, Italy

    Giambattista Guaitoli & Maria Paola Costi

  3. Naxospharma, “Discovery Chemistry and Biotech”, 20020, Cesate, MI, Italy

    Paolo Lombardi

Authors
  1. Gaetano Marverti
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  2. Giambattista Guaitoli
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  3. Alessio Ligabue
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  4. Chiara Frassineti
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  5. Maria Giuseppina Monti
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  6. Paolo Lombardi
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  7. Maria Paola Costi
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Corresponding authors

Correspondence to Gaetano Marverti or Maria Paola Costi.

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Marverti, G., Guaitoli, G., Ligabue, A. et al. Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells. Amino Acids 42, 641–653 (2012). https://doi.org/10.1007/s00726-011-1039-3

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  • DOI: https://doi.org/10.1007/s00726-011-1039-3

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