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Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi017
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Oxford University Press
Received July 28, 2004
Revised November 3, 2004
Accepted January 8, 2005

CANCER BIOLOGY

Antineoplastic cyclic astin analogues kill tumor cells via caspase-mediated induction of apoptosis

Rosanna Cozzolino 1, Pasquale Palladino 2, Filomena Rossi 2, Gaetano Calì 3, Ettore Benedetti 2, and Paolo Laccetti 1*

1 Department of Biological Chemistry, University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy
2 Department of Biological Chemistry, University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy; CIRPEB and IBB-CNR, University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy
3 CNR-IEOS c/o Department of Cellular and Molecular Biology and Pathology "L. Califano", University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy

* To whom correspondence should be addressed.
Paolo Laccetti, E-mail: paolo.laccetti{at}unina.it


  Abstract

Astins, a family of cyclopentapeptides, isolated from the roots of a medicinal plant Aster Tataricus (Compositae), show antitumor activity. Their chemical structures consist of a 16-membered ring system containing a unique {beta},{gamma}-dichlorinated proline [Pro(Cl2)], other non-coded aminoacid residues, and a cis conformation in one of the peptide bonds. The {beta},{gamma}-dichlorinated proline residue is considered to play an important role in their antineoplastic activities in vitro on nasopharynx carcinoma (KB) cells and in vivo on sarcoma 180 ascites and P388 lymphocytic leukemia in mice. The acyclic astins without Pro(Cl2) do not show antitumor activity against S-180 ascites in vivo, suggesting that the cyclic nature of astins plays an important role in their antitumor activities. We synthesized new astin-related cyclopeptides differing from the natural product for the presence of some non-proteinogenic aminoacid residues: Aib, Abu, -S({beta}3)-hPhe and a peptide bond surrogate (-SO2-NH-) and we tested for their antitumor effect. We observed cytotoxic effects of the newly synthetized cyclic astins, but not with the acyclic analogue astins. We also observed that the cyclic astin induced apoptosis in a human papillary thyroid carcinoma cell line (NPA cell line) and that apoptotis was associated with activation of caspases. The caspase family inhibitor, Z-Val-Asp-(OMe)-FMK, protected NPA cells from cyclic analogue astin induced apoptosis. To determine which caspase was specifically activated, we assayed caspase activity in astin-treated cells in the presence of specific caspase-8 -9 or -3 inhibitors, Z-IETD-FMK, Z-LEHDFMK, Z-DEVD-FMK, which inhibit caspase-8, -9 and -3, respectively.

The data presented here show selective antineoplastic properties of the newly synthetized cyclic astins, and suggest, for the first time, a mechanism for their antineoplastic action through the activation of apoptotic pathway.


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