Conjugation of doxorubicin to cell penetrating peptides sensitizes human breast MDA-MB 231 cancer cells to endogenous TRAIL-induced apoptosis

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.

Small Efficient Cell-penetrating Peptides Derived from Scorpion Toxin Maurocalcine

“…Interestingly, removing the last 8 C-terminal amino acids of MCa had little impact on the cell penetration properties (if one compares MCa UF14 -25 -C with MCa UF14 -33 -C). Similarly, the removal of the amino acid region His 6 -Asn 13 did not drastically change cell penetration properties (MCa UF6 -25 -C versus MCa UF14 -25 -C). Second, all peptides appeared to behave better than the reference peptide MCa UF1-33 -C, suggesting that sequence truncation of MCa UF may represent a potent strategy to define more efficient CPPs.…”

“…Studies that were undertaken to demonstrate the ability of MCa to reach its target showed that (i) MCa triggers Ca 2ϩ release from the SR a few seconds after its application in the extracellular medium (5) and (ii) intracellular accumulation of fluorescent-streptavidin occurs if it incubated first with biotinylated MCa (10). Since these pioneering studies, MCa or analogues thereof proved powerful vectors for the cell entry of proteins, peptides (11), nanoparticles, or drugs such as doxorubicin (12)(13)(14)(15). Although the mode of cell penetration of MCa may vary according to cargo nature, cell type, or chemical linkage employed, the data gathered so far suggest that the peptide may enter cells according to two priming steps onto the plasma membrane: first an interaction with proteoglycans with an affinity in the micromolar range, followed by a second interaction with negatively charged lipids which occurs with greater affinity (16,17).…”

Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

“…Efficient induction of apoptosis by CPP-DOX was found in the human breast cancer cell line MDA-MB-231. 8,9 In addition, various CPPdrug conjugates have also been developed to improve antitumor efficacy.…”

Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts

“…our recent study showed that oxaliplatin enhances Trail sensitivity by clustering death receptors into lipid rafts (7). aroui et al reported that doxorubicin sensitizes breast cancer cells to Trail by triggering lipid raft aggregation (17). doxorubicin and epirubicin are both anthracyclines, but whether epirubicin is capable of regulating lipid rafts and thus enhancing the sensitivity of gastric cancer cells to Trail remains to be determined.…”