Journal Article

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

Rosanna Cozzolino, Pasquale Palladino, Filomena Rossi, Gaetano Calì, Ettore Benedetti and Paolo Laccetti

in Carcinogenesis

Volume 26, issue 4, pages 733-739
Published in print April 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI:
Antineoplastic cyclic astin analogues kill tumour cells via caspase-mediated induction of apoptosis

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Astins, a family of cyclopentapeptides, isolated from the roots of a medicinal plant Aster tataricus (Compositae), show antitumour activity. Their chemical structures consist of a 16-membered ring system containing a unique β,γ-dichlorinated proline [Pro(Cl2)], other non-coded amino acid residues, and a cis conformation in one of the peptide bonds. The β,γ-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 leukaemia in mice. The acyclic astins without Pro(Cl2) do not show antitumour activity against S-180 ascites in vivo, suggesting that the cyclic nature of astins plays an important role in their antitumour activities. We synthesized new astin-related cyclopeptides differing from the natural product for the presence of some non-proteinogenic amino acid residues: Aib, Abu, -S(β3)-hPhe and a peptide bond surrogate (−SO2−NH−) and we tested for their antitumour effect. We observed cytotoxic effects of the newly synthesized 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 and 8, 9 or 3 inhibitors, i.e. Z–IETD–FMK, Z–LEHD–FMK Z–DEVD–FMK, which inhibit caspases 8, 9 and 3, respectively. The data presented here show selective antineoplastic properties of the newly synthesized cyclic astins, and suggest, for the first time, a mechanism for their antineoplastic action through the activation of apoptotic pathway.

Keywords: AFC, 7-amino-4-trifluoromethyl-coumarin; DMSO, dimethyl sulfoxide; FITC, fluorescein isothiocyanate; FMK, fluoromethylketone; Hoechst 33258, 2′(4Hydroxyphenyl) 5-(4-methyl-1-piperazynil) – 2,5′-bi (1H-benzimidazol)-6-(1-methyl-4piperazyl)benzimidazole trihydrochloride; MTT, 3-(4,5-dimethyltiazol-z-yl) 2,5-diphenyltetrazolium bromide (thiazolyl blue); PI, propidium iodide; Z-DEVD-FMK, Z-Asp-(OMe)-Glu-(OMe)-Val-Asp(OMe)-fluoromethylketone; Z-IETD-FMK, Z-Ile-Glu-Thr-Asp-(OMe)-fluoromethylketone; Z-LEHD-FMK, Z-Leu-Glu-(OMe)-Asp-(OMe)-fluoromethylketone; Z-VAD-FMK, Z-Val-Asp-(OMe)-fluoromethylketone; Pro(Cl2), β,γ-dichlorinated proline

Journal Article.  5072 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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