Conjugation of doxorubicin to cell penetrating peptides sensitizes human breast MDA-MB 231 cancer cells to endogenous TRAIL-induced apoptosis |
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Authors: | Sonia Aroui Souhir Brahim Jocelyne Hamelin Michel De Waard Jacqueline Bréard Abderraouf Kenani |
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Institution: | 1. Unité 05/UR/09-09, Mécanismes Moléculaires et Pathologies, Faculté de Médecine de Monastir, Monastir, 5019, Tunisie 2. INSERM U836, Grenoble Institute of Neuroscience, Calcium Channels, Functions and Pathologies, Site santé de la Tronche, BP 170, 38042, Grenoble Cedex 9, France 3. Université Joseph Fourier, BP 170, 38042, Grenoble Cedex 9, France 4. INSERM U749, Faculté de Pharmacie, 5 rue J.B. Clément, 92290, Chatenay-Malabry, France
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Abstract: | Previous work from our laboratory has shown that coupling doxorubicin (Dox) to cell penetrating peptides (Dox–CPPs) is a good
strategy to overcome Dox resistance in MDA-MB 231 breast cancer cells. We also reported that, in contrast to unconjugated
Dox-induced cell death, the increase in apoptotic response does not involve the mitochondrial apoptotic pathway. In this study,
we demonstrate that both Dox and Dox–CPPs can increase the density of the TRAIL receptors DR4 and DR5 at the plasma membrane
and moderately sensitize MDA-MB 231 cells to exogeneously added recombinant TRAIL, as has already been shown for other chemotherapeutic
drugs. Moreover, we show that Dox–CPPs, used alone, induce the clustering of TRAIL receptors into ceramide-enriched membrane
lipid rafts, a property not shared by unconjugated Dox and that this process is due to the generation of ceramide during Dox–CPPs
treatment. In addition, MDA-MB 231 cells were found to express TRAIL and we show that the increased apoptotic rate induced
by Dox–CPPs is due to the sensitization of MDA-MB 231 cells to endogenous TRAIL. The capacity of Dox–CPPs to sensitize cancer
cells to physiologic amounts of TRAIL suggests that, in addition to their efficiency in combination chemotherapy, these compounds
might increase the response of tumor cells to cytotoxic lymphocyte-mediated killing via TRAIL. |
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