A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors

Isabella Orienti, Federica Francescangeli, Maria Laura De Angelis, Katia Fecchi, Lucilla Bongiorno-Borbone, Michele Signore, Angelo Peschiaroli, Alessandra Boe, Alessandro Bruselles, Angelita Costantino, Adriana Eramo, Valentina Salvati, Giovanni Sette, Paola Contavalli, Lello Zolla, Toshihiko Oki, Toshio Kitamura, Massimo Spada, Alessandro Giuliani, Marta BaiocchiFilippo La Torre, Gerry Melino, Marco Tartaglia, Ruggero De Maria, Ann Zeuner

Research output: Contribution to journalArticle

Abstract

Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention.

Original languageEnglish
Pages (from-to)529
JournalCell death & disease
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 23 2019

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