Suppression of human prostate tumor growth in mice by a cytolytic D-, L-amino Acid Peptide: membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion.
Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D- and L-amino acids (diastereomer), which targets both androgen-independent and androgen-dependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all l-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.
Papo
Niv
N
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Braunstein
Amir
A
Eshhar
Zelig
Z
Shai
Yechiel
Y
D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000502:physiology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D009336:Necrosis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013237:Stereoisomerism; D023041:Xenograft Model Antitumor Assays
D000596:Amino Acids; D000728:Androgens; D005452:Fluoresceins; D009842:Oligopeptides; D004317:Doxorubicin; D003520:Cyclophosphamide; D017430:Prostate-Specific Antigen; C007740:fluorexon