Elisidepsin Interacts Directly with Glycosylceramides in the Plasma Membrane of Tumor Cells to Induce Necrotic Cell Death

Abstract

Plasma membrane integrity is essential for cell life. Any major break on it immediately induces the death of the affected cell. Different molecules were described as disrupting this cell structure and thus showing antitumor activity. We have previously defined that elisidepsin (Irvalec®, PM02734) inserts and self-organizes in the plasma membrane of tumor cells, inducing a rapid loss of membrane integrity, cell permeabilization and necrotic death. Here we show that, in sensitive HCT-116 colorectal cells, all these effects are consequence of the interaction of elisidepsin with glycosylceramides in the cell membrane. Of note, an elisidepsin-resistant subline (HCT-116-Irv) presented reduced levels of glycosylceramides and no accumulation of elisidepsin in the plasma membrane. Consequently, drug treatment did not induce the characteristic necrotic cell death. Furthermore, GM95, a mutant derivative from B16 mouse melanoma cells lacking ceramide glucosyltransferase (UGCG) activity and thus the synthesis of glycosylceramides, was also resistant to elisidepsin. Over-expression of UGCG gene in these deficient cells restored glycosylceramides synthesis, rendering them sensitive to elisidepsin, at a similar level than parental B16 cells. These results indicate that glycosylceramides act as membrane targets of elisidepsin, facilitating its insertion in the plasma membrane and the subsequent membrane permeabilization that leads to drug-induced cell death. They also indicate that cell membrane lipids are a plausible target for antineoplastic therapy.

Bioactive Compounds from Marine Heterobranchs

“…Elisidepsin ( 357 ) also underwent clinical development after showing IC 50 values between 0.4 and ~9 μM in a 23 cancer cell lines, including breast, colon, head and neck, lung, ovary, pancreas, prostate, and melanoma types [ 810 , 811 , 812 ]. Elisidepsin ( 357 ) acts at the cell membrane level, interacting directly with glycosylceramides in the membrane of cancer cells, while inducing necrosis-like cell death in the yeast Saccharomyces cerevisiae [ 813 , 814 , 815 ]. Elisidepsin ( 357 ) is active in vivo against human melanoma, liver, pancreas, breast, and prostate cancer xenografts [ 816 ].…”

Natural Cyclic Peptides as an Attractive Modality for Therapeutics: A Mini Review

“…The anticancer compound elisidepsin is an analogue of kahalalide F, which exhibited in vitro activity against several tumor cell lines such as breast, colon, pancreas, prostate, and lung [ 54 , 55 , 56 ]. It showed promising results for further clinical studies of cancer therapy.…”

Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications

“…Elisidepsin was shown to insert into the plasma membrane of cancer cells and reorganize itself in the membrane; this caused the disruption of the plasma membrane and resulted in a loss of integrity of the membrane, causing necrotic death of cells [ 192 , 205 ]. Molina-Guijarro et al [ 206 ] elucidated the detailed mechanism of loss of membrane integrity by elisidepsin and identified that glycosylceramides act as membrane targets of elisidepsin. Glycosylceramides in cells facilitates the insertion of elisidepsin, resulting in membrane destabilization and cell death.…”