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

Abstract

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)

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

“…Their mode of action can vary. It was shown that they can induce necrosis after plasma membrane disruption, depending on their L-or D-chirality, 52,53 apoptosis by the upregulation of caspases, 54 the influx of extracellular Ca 2 + , Ca 2 + -mediated DJm disruption and mitochondrial O 2 $ À generation. 55 However, the cationic peptide (KLAKLAK) 2 has been reported to have a potency that is too low for it to be used as an effective anticancer drug.…”

Cetuximab Attenuates Metastasis and u-PAR Expression in Non–Small Cell Lung Cancer: u-PAR and E-Cadherin are Novel Biomarkers of Cetuximab Sensitivity

“…Thus, Cetuximab adds to the compounds able to inhibit primary tumor growth and metastasis. For example, Papo and colleagues (39) observed that host defense-derived cytolytic cationic polypeptides kill cancer cells via cytoplasmic membrane depolarization, and the resulting membrane disruption can provide a therapeutic means of inhibiting both tumor growth and metastasis of various cancers.…”

Assembly of the TLR2/6 Transmembrane Domains Is Essential for Activation and Is a Target for Prevention of Sepsis

“…The cells were then incubated for 2 h before adding to each well 50 ml 2,3-bis-2H-tetrazolium-5-carboxanilide inner salt reaction solution (Biological Industries). Viability was determined as described previously (19,20). The LC 50 (the concentration at which 50% of the cells die) for each peptide was obtained from the dose-dependent cell viability curves.…”