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Open AccessArticle

Liposomes Loaded with the Proteasome Inhibitor Z-Leucinyl-Leucinyl-Norleucinal Are Effective in Inducing Apoptosis in Colorectal Cancer Cell Lines

DIMES, Department of Experimental Medicine, Human Anatomy, University of Genoa, 16132 Genoa, Italy
IRCCS Ospedale Policlinico San Martino, UO Bioterapie, 16132 Genoa, Italy
Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
Authors to whom correspondence should be addressed.
Membranes 2020, 10(5), 91;
Received: 17 February 2020 / Revised: 19 April 2020 / Accepted: 29 April 2020 / Published: 3 May 2020
(This article belongs to the Special Issue Membranes: 10th Anniversary)
Colorectal cancer (CRC) is one of the main causes of cancer-related death in developed countries. Targeted therapies and conventional chemotherapeutics have been developed to help treat this type of aggressive cancer. Among these, the monoclonal antibodies cetuximab (Cxm) and panitumumab specifically target and inactivate the signaling of ERBB1 (EGF receptor), a key player in the development and progression of this cancer. Unfortunately, these antibodies are effective only on a small fraction of patients due to primary or secondary/acquired resistance. However, as ERBB1 cell surface expression is often maintained in resistant tumors, ERBB1 can be exploited as a target to deliver other drugs. Liposomes and immunoliposomes are under intensive investigation as pharmaceutical nanocarriers and can be functionalized with specific antibodies. In this study, we first investigated the anti-cancer activity of a cell permeable tripeptide, leucine-leucin-norleucinal (LLNle), an inhibitor of gamma-secretase and proteasome, in three different CRC cell lines that express ERBB1. We formulated LLNle-liposomes and Cxm-conjugated LLNle-loaded liposomes (LLNle-immunoliposomes) and evaluated their efficacy in inhibiting cell survival. Despite similar pro-apoptotic effects of free LLNle and LLNle-liposomes, immunoliposomes-LLNle were significantly less effective than their unconjugated counterparts. Indeed, immunoliposomes-LLNle were readily internalized and trafficked to lysosomes, where LLNle was likely trapped and/or inactivated. In conclusion, we demonstrated that LLNle was readily delivered to CRC cell lines by liposomes, but immunoliposomes-LLNle failed to show significant anti-cancer activity. View Full-Text
Keywords: liposomes; colorectal cancer; ERBB1; cetuximab; proteasome liposomes; colorectal cancer; ERBB1; cetuximab; proteasome
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Cortese, K.; Marconi, S.; Aiello, C.; Gagliani, M.C.; Pilato, S.; Zappacosta, R.; Fontana, A.; Castagnola, P. Liposomes Loaded with the Proteasome Inhibitor Z-Leucinyl-Leucinyl-Norleucinal Are Effective in Inducing Apoptosis in Colorectal Cancer Cell Lines. Membranes 2020, 10, 91.

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