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.
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.
Papo
Niv
N
Departments of Biological Chemistry, Biological Regulation, Veterinary Resources, and Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Seger
Dalia
D
Makovitzki
Arik
A
Kalchenko
Vyacheslav
V
Eshhar
Zelig
Z
Degani
Hadassa
H
Shai
Yechiel
Y
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008239:Lysine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D010455:Peptides; D010718:Phosphatidylserines; D017430:Prostate-Specific Antigen; D007930:Leucine; D008239:Lysine