Inhibition of tumor growth and elimination of multiple metastases in human prostate and breast xenografts by systemic inoculation of a host defense-like lytic peptide

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-05, Vol.66 (10), p.5371-5378
• Main Authors: PAPO, Niv, SEGER, Dalia, MAKOVITZKI, Arik, KALCHENKO, Vyacheslav, ESHHAR, Zelig, DEGANI, Hadassa, SHAI, Yechiel
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adenocarcinoma - secretion; Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Female; Humans; Leucine - analogs & derivatives; Leucine - pharmacokinetics; Leucine - pharmacology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lysine - analogs & derivatives; Lysine - pharmacokinetics; Lysine - pharmacology; Male; Medical sciences; Membrane Potentials - drug effects; Mice; Mice, SCID; Neoplasm Metastasis; Peptides - pharmacokinetics; Peptides - pharmacology; Pharmacology. Drug treatments; Phosphatidylserines - metabolism; Prostate-Specific Antigen - secretion; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - secretion; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-4569

We report on a short host defense-like peptide that targets and arrests the growth of aggressive and hormone-resistant primary human prostate and breast tumors and prevents their experimental and spontaneous metastases, respectively, when systemically inoculated to immunodeficient mice. These effects are correlated with increased necrosis of the tumor cells and a significant decrease in the overall tumor microvessel density, as well as newly formed capillary tubes and prostate-specific antigen secretion (in prostate tumors). Growth inhibition of orthotopic tumors derived from stably transfected highly fluorescent human breast cancer cells and prevention of their naturally occurring metastases were visualized in real time by using noninvasive whole-body optical imaging. The exclusive selectivity of the peptide towards cancer derives from its specific binding to surface phosphatidylserine and the killing of the cancer cells via cytoplasmic membrane depolarization. These data indicate that membrane disruption can provide a therapeutic means of inhibiting tumor growth and preventing metastases of various cancers.