An Artificially Designed Pore-forming Protein with Anti-tumor Effects

Ellerby, H. Michael; Lee, Sannamu; Ellerby, Lisa M.; Chen, Sylvia; Kiyota, Taira; Río, Gabriel del; Sugihara, Gohsuke; Sun, Yan Mei; Bredesen, Dale E.; Arap, Wadih; Pasqualini, Renata

doi:10.1074/jbc.m300474200

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…At present, many proteins from different sources have been found to possess antitumor activity (28)(29)(30)(31)(32). Of these, fungal proteins are the major one, in which fungal immunomodulatory protein (FIP), ribosome-inactivating protein (RIP), lectins, and glycoproteins, are involved, due to their favorable effect against a variety of tumors (33).…”

Section: Discussionmentioning

confidence: 99%

“…3D), showing that PVP had no effect on the tumor cells. However, after exposure to a concentration gradient of pPeOp (30,45, 60, 90 and 120 µg/ml), MC-4 was significantly damaged by cell shrinkage, membrane blebbing, boundary split or aggregation, and underwent an increasing cell death with increasing pPeOp concentrations (Fig. 3E-I).…”

Section: Morphological Changes Induced By Ppeopmentioning

confidence: 99%

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A PVP-extract fungal protein of Omphalia lapideacens and its antitumor activity on human gastric tumors and normal cells

Chen

Lu²,

Lin³

et al. 2011

Oncol Rep

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Abstract. Omphalia lapidescens is an important medicinal fungus as well as traditional Chinese medicine used for disease treatment. It is mainly used as a vermifuge for anthelmintic therapy, but it has not been hitherto reported to possess antitumor activity. In this study, a purified bioactive protein in O. lapidescens (pPeOp) was obtained using polyvinylpyrrolidone (PVP) followed by gel filtration chromatography. To evaluate the in vitro antitumor activity of pPeOp in human gastric tumor cells (MC-4 and SGC-7901) and normal cells (MC-1), MTT assay and FCM assay were used and the morphological changes, cell viability, cell death rate and cell apoptosis rate of MC-4, SGC-7901 and MC-1 cells were estimated. The results showed that pPeOp could significantly reduce the cell viability of MC-4 and SGC-7901 cells in a concentration-dependent manner, with IC 50 values of 236.05 and 156.28 µg/ml, respectively. The morphological observation also indicated a similar result. In FCM assays, a significant increase of cell death rate and cell apoptosis rate of the tumor cells were observed, indicating probable necrosisinducing effects and/or apoptosis-inducing effects of pPeOp. Importantly, there was no significant effect of pPeOp on MC-1 cells in each assay, showing that pPeOp has no adverse effects on the normal cells. In conclusion, pPeOp is a newly discovered bioactive protein in O. lapidescens and this is the first report on antitumor activity of such a fungal protein. This may provide a meaningful basis for developing a new protein drug for treatment against cancer, especially gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Morphological Changes Induced By Ppeopmentioning

confidence: 99%

A PVP-extract fungal protein of Omphalia lapideacens and its antitumor activity on human gastric tumors and normal cells

Chen

Lu²,

Lin³

et al. 2011

Oncol Rep

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“…These studies include (i) systemic treatments of solid tumors with lytic peptides, but only when they were conjugated to homing (targeting) domains or when used as propeptides (12,27), mainly because the lytic entity is inactivated in serum and lacks tumor specificity; (ii) treatment of ovarian cancer with magainin and its D-amino acid enantiomer, but only when injected i.p. at high doses (28); and (iii) an intratumor administration of a 69-amino-acid pore-forming peptide against human breast cancer xenografts (11). Importantly, all of these treatments influenced only slightly, if at all, disseminated metastases (27) because of either limited intrinsic local activity or their inability to reach sizeable metastases in the intact animals.…”

Section: Introductionmentioning

confidence: 99%

“…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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“…However, inspiration might be drawn from peptide studies of other groups, e.g. the creation of chimeric peptides, linkage to known receptor-ligands [69], hormone ligands [70, 71] or other nano carriers, as previously done with Melittin [72, 73]. …”

Section: Resultsmentioning

confidence: 99%

Identification of a novel lytic peptide for the treatment of solid tumours

et al. 2014

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ABSTRACT:Originally known as host defence peptides for their substantial bacteriotoxic effects, many cationic antimicrobial peptides also exhibit a potent cytotoxic activity against cancer cells. Their mode of action is characterized mostly by electrostatic interactions with the plasma membrane, leading to membrane disruption and rapid necrotic cell death.In this work, we have designed a novel cationic peptide of 27 amino acids (Cypep-1), which shows efficacy against a number of cancer cell types, both in vitro and in vivo, while normal human fibroblasts were significantly less affected. Surface plasmon resonance experiments as well as liposome leakage assays monitored by fluorescence spectroscopy revealed a substantial binding affinity of Cypep-1 to negatively charged liposomes and induced significant leakage of liposome content after exposure to the peptide. The observed membranolytic effect of Cypep-1 was confirmed by scanning electron microscopy (SEM) as well as by time-lapse confocal microscopy. Pharmacokinetic profiling of Cypep-1 in rats showed a short plasma half-life after i.v. injection, followed mainly by retention in the liver, spleen and kidneys. Extremely low concentrations within the organs of the central nervous system indicated that Cypep-1 did not pass the blood-brain-barrier.Local treatment of 4T1 murine mammary carcinoma allografts by means of a single local bolus injection of Cypep-1 led to a significant reduction of tumour growth in the following weeks and prolonged survival. Detailed histological analysis of the treated tumours revealed large areas of necrosis.In sum, our findings show that the novel cationic peptide Cypep-1 displays a strong cytolytic activity against cancer cells both in vitro and in vivo and thus holds a substantial therapeutic potential.

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An Artificially Designed Pore-forming Protein with Anti-tumor Effects

Cited by 17 publications

References 36 publications

A PVP-extract fungal protein of Omphalia lapideacens and its antitumor activity on human gastric tumors and normal cells

A PVP-extract fungal protein of Omphalia lapideacens and its antitumor activity on human gastric tumors and normal cells

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

Identification of a novel lytic peptide for the treatment of solid tumours

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