Abstract
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.
Highlights
Liposomes are colloids formed by the enclosure of aqueous core into a spherical shaped phospholipidic bilayer
To test the hypothesis that LLNle was able to inhibit Colorectal cancer (CRC) cell survival by inducing apoptosis, to what we observed in Glioblastoma (GBM) cells, we performed an MTT assay after 72 h of treatment with several concentrations of this substance
Our experiments showed that both LLNleliposomes and an equivalent concentration of free LLNle were able to achieve a survival inhibition of about 80% (2.5, 2.0 and 0.7 μ M LLNle for Caco-2, GP2d and LoVo, respectively) and were able to significantly inhibit cell survival (p < 0.001) in the three cell lines tested, compared to medium supplemented with phosphate-buffered saline (PBS) or DMSO treated controls, respectively
Summary
Liposomes are colloids formed by the enclosure of aqueous core into a spherical shaped phospholipidic bilayer. It was reported that these Cxm-liposomes were able to inhibit skin cancer cell growth and to improve patient compliance by delivering the highly hydrophilic chemotherapeutic 5-fluorouracil (5-FU). This delivery system was shown to favor skin penetration [15]. We intended to evaluate a novel combination of Cxm with the proteasome inhibitor tripeptide LLNLe in order to limit its toxicity towards normal cells improving cancer cell targeting efficiency using three different CRC cell lines expressing the ERBB1 receptor
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
