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p21^WAF1-derived Peptides Linked to an Internalization Peptide Inhibit Human Cancer Cell Growth¹

Molecular Pharmacology Unit, Istituto di Ricerche Farmacologiche "Mario Negri" via Eritrea 62, 20157 Milan, Italy

We tested the ability of synthetic peptides derived from p21^WAF1, fused to the internalization peptide sequence derived from Antennapedia, to inhibit the growth of cancer cells in two human ovarian cancer cell lines expressing wild-type p53 or not. Two fused peptides corresponding to p21^WAF1 regions 17–33 and 63–77 inhibited cell growth in both cell lines while the same peptides without the internalization sequence were inactive. The fused peptides prevented growth at concentrations which inhibited cyclin-dependent kinase 2 and cdc2 activity, thus demonstrating that the peptides act by mimicking the action of p21^WAF1 on kinases. This study illustrates the potential pharmacological use of small peptides fused with the Antennapedia internalization sequence in proliferative disorders. The approach may be extended to other diseases in which cell penetration of a peptide may be of therapeutic benefit. More stable drug-like molecules with better pharmacological properties could be designed based on the results obtained with peptides.

¹ This work was partially supported by Progetto Strategico Ciclo Cellulare e Apoptosi 96.01026.st74 and by the Italian Association for Cancer Research.

² To whom requests for reprints should be addressed. Phone: 39-2-39014472; Fax: 39-2-3546277; E-mail: broggini@irfmn.mnegri.it.

Received 1/30/97. Accepted 2/28/97.

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