Membrane Disrupting Lytic Peptide Conjugates Destroy Hormone Dependent and Independent Breast Cancer Cells in vitro and in vivo

Leuschner, Carola; Enright, Frederick M.; Gawrońska, Barbara; Hansel, William

doi:10.1023/a:1022169525521

Cited by 62 publications

(56 citation statements)

References 14 publications

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“…However, increased TUNEL-staining was observed in ovaries of mice treated with [DLys6]GnRH-4EBP1-WT peptide. Another study that evaluated a GnRH-conjugated membrane-disrupting peptide in a breast cancer xenograft model likewise noted some death of ovarian granulosa cells (37).…”

Section: Discussionmentioning

confidence: 98%

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

Guo

Barengo

et al. 2009

Clinical Cancer Research

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Purpose: A critical step of protein synthesis involves the liberation of the mRNA capbinding translation initiation factor eIF4E from 4EBP inhibitory binding proteins, and its engagement to the scaffolding protein eIF4G. eIF4E is a candidate target for cancer therapy because it is overexpressed or activated in many types of tumors and has tumorigenic properties. Our aim was to design and evaluate 4EBP-based peptides for their antitumor activity in ovarian cancer. Experimental Design: The ability of peptides to bind and inhibit eIF4E was determined by immunoprecipitation and by assaying cap-dependent reporter synthesis. To target ovarian tumors, the lead candidate 4EBP peptide was fused to an analog of gonadotropin-releasing hormone (GnRH). Cellular uptake of peptide, and effects on cell viability and cell death were determined. The antitumor activity of fusion peptide was evaluated in female nude mice bearing i.p. ovarian tumor xenografts. Results: 4EBP-based peptides bound eIF4E, prevented eIF4E from binding eIF4G, and inhibited cap-dependent translation. GnRH agonist-4EBP fusion peptide was taken up by, and inhibited the growth of, GnRH receptor-expressing tumor cells, but not receptornegative cells. Intraperitoneal tumor burden was significantly smaller in mice treated with fusion peptide than in mice treated with saline (P < 0.001). Ascites was also reduced in peptide-treated mice. Significant cytotoxic effects to host tissues were not observed. On the other hand, treatment with GnRH agonist alone did not inhibit tumor growth or ascites. Conclusion: Because ovarian cancer is rarely cured by conventional chemotherapies, GnRH-4EBP fusion peptide may be of therapeutic potential for treatment of this disease.

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Section: Discussionmentioning

confidence: 98%

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

Guo

Barengo

et al. 2009

Clinical Cancer Research

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“…In that regard, host defense-derived cytolytic cationic polypeptides, which were initially discovered due to their role in clearance of bacteria ( for reviews, see refs. [4][5][6][7], seem to overcome these limitations via a yet unknown non-receptormediated mechanism (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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

Seger²,

et al. 2006

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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 immuodeficient 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. (Cancer Res 2006; 66(10): 5371-8)

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“…These peptides have a central role in the innate immunity of all of the organisms, including insects, amphibians, and mammals (18). Examples include human defensins (19 -21), cecropins (22), cecropin-magainin hybrids (23,24), magainins (14), peptides conjugated to homing domains (15)(16)(17), propeptides (25), and others (26,27). These peptides preferentially bind and disrupt negatively charged phospholipid membranes, the major component of the bacterial cytoplasmic membrane.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Papo

Braunstein²,

Eshhar³

et al. 2004

Cancer Research

112

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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 androgendependent 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.

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Membrane Disrupting Lytic Peptide Conjugates Destroy Hormone Dependent and Independent Breast Cancer Cells in vitro and in vivo

Cited by 62 publications

References 14 publications

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

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

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

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