Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma

• Published in: Biochimica et biophysica acta Vol. 1858; no. 12; pp. 3195 - 3204
• Main Authors: Hilchie, Ashley L., Sharon, Andrew J., Haney, Evan F., Hoskin, David W., Bally, Marcel B., Franco, Octavio L., Corcoran, Jennifer A., Hancock, Robert E.W.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2016
• Subjects: Animals; Anti-cancer peptide; Antineoplastic Agents - pharmacology; Breast cancer; Broad-spectrum; Cell Line, Tumor; Cell Membrane - drug effects; Circular Dichroism; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Synergism; Female; Humans; Leukemia; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Membrane lysis; Mice; Mice, Inbred BALB C; Peptides - pharmacology; Synergy; Wasp Venoms - pharmacology; AML; HMEC; Q2D; DMSO; Leukemia; IP; POPS; Breast cancer; LUV; PBMC; Broad-spectrum; ACP; LDH; Anti-cancer peptide; Membrane lysis; POPC; PI; MDR; Synergy; T-ALL; Q7D
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2016.09.021

Anti-cancer peptides (ACPs) are small cationic and hydrophobic peptides that are more toxic to cancer cells than normal cells. ACPs kill cancer cells by causing irreparable membrane damage and cell lysis, or by inducing apoptosis. Direct-acting ACPs do not bind to a unique receptor, but are rather attracted to several different molecules on the surface of cancer cells. Here we report that an amidated wasp venom peptide, Mastoparan, exhibited potent anti-cancer activities toward leukemia (IC50~8–9.2μM), myeloma (IC50~11μM), and breast cancer cells (IC50~20–24μM), including multidrug resistant and slow growing cancer cells. Importantly, the potency and mechanism of cancer cell killing was related to the amidation of the C-terminal carboxyl group. Mastoparan was less toxic to normal cells than it was to cancer cells (e.g., IC50 to PBMC=48μM). Mastoparan killed cancer cells by a lytic mechanism. Moreover, Mastoparan enhanced etoposide-induced cell death in vitro. Our data also suggest that Mastoparan and gemcitabine work synergistically in a mouse model of mammary carcinoma. Collectively, these data demonstrate that Mastoparan is a broad-spectrum, direct-acting ACP that warrants additional study as a new therapeutic agent for the treatment of various cancers. [Display omitted] •Mastoparan-NH2 is a broad-spectrum, direct-acting, anti-cancer peptide.•Mastoparan potency and mechanism of action is related to its C-terminal amidation.•Mastoparan enhances etoposide-induced cytotoxicity in vitro.•Systemically-delivered Mastoparan and gemcitabine may work synergistically in vivo.