Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Abstract

Previously, we reported that intratumor or systemic inoculation of a cationic 15-mer, innate immunity-like lytic peptide composed of D-and L-amino acids ([D]-K 6 L 9 ) caused growth arrest of 22RV1 prostate carcinoma xenografts in a mouse model. However, despite its therapeutic potential, this peptide has significant systemic toxicity at concentrations slightly higher than the therapeutic one. Here, we used the acidic environment created by solid tumors as a trigger to activate anticancer lytic peptides by making them cationic only at low pH levels. We achieved this selectivity by substituting lysines (pKa, f10.5) for histidines (pKa, f6.1) in the parental peptide [D]-K 6 L 9 . Histidine is protonated below pH 7. For that purpose, we replaced either three or all six lysines in the parental peptide with histidines to obtain the peptides [D]-K 3 H 3 L 9 and [D]-H 6 L 9 . Interestingly, in vitro experiments showed pH-dependent activity only with [D]-H 6 L 9 mainly toward cancer cell lines. However, both peptides showed reduced systemic toxicity compared with the parental peptide. Intratumor and systemic inoculation of these peptides resulted in a significant decrease in the 22RV1 prostate cancer tumor volume and systemic secretion of prostate-specific antigen in a xenograft mice model. Moreover, histologic modifications revealed a significant reduction in new blood vessels selectively in tumor tissues after treatment with the peptides compared with the untreated tumors. The lytic mode of action of these new peptides, which makes it difficult for the cancer cells to develop resistance, and their selective and pH-dependent activity make them potential candidates for treatment of solid cancer tumors.

Effect of PhoP-PhoQ Activation by Broad Repertoire of Antimicrobial Peptides on Bacterial Resistance

“…The error bars represent the standard error. The peptide's amphipaticity also seems to contribute to its activating ability because the three all-L-amino acid peptides (LL-37, melittin, and L-K 6 L 9 ) with the highest experimental hydrophobicity also have an ␣-helical structure in membranes (41,42). Note that all of the peptides can reach the inner membrane to interact with PhoQ (Fig.…”

Ultrashort Peptide Bioconjugates Are Exclusively Antifungal Agents and Synergize with Cyclodextrin and Amphotericin B

“…Peptide concentrations ranged from 3.12 to 200 M. The cells then were incubated for 16 h, and the medium was replaced with 100 l fresh medium and 50 l of 2,3-bis-2H-tetrazolium-5-carboxanilide inner salt (XTT) reaction solution (Biological Industries). Viability was determined as described previously (23,34). The LC 50 for each peptide was obtained from the dose-dependent cell viability curves.…”

Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide-mediated liposomal delivery system

“…We made a bold assumption that drug delivery system modified with histidine-rich antimicrobial peptides could yield considerable transfection efficiency. In this work, we utilized peptide [D]-H 6 L 9 , a pH-dependent antimicrobial peptide reported by Makovitzki et al [27], and tethered it onto the surface of liposomes (Fig.1). Liposome was consequently loaded with antagomir-10b (metastasis inhibitor) and paclitaxel (PTX, cytotoxic reagent) for the treatment of murine metastatic mammary tumor models.…”