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. 2013 Mar 20;11(3):944-59.
doi: 10.3390/md11030944.

Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-derived Marine Compound

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Free PMC article

Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-derived Marine Compound

Maria Serova et al. Mar Drugs. .
Free PMC article

Abstract

Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.

Figures

Figure 1
Figure 1
Antiproliferative effects of elisidepsin in a panel of human cancer cell lines with their associated mutations in KRAS and BRAF genes and EGFR overexpression status. IC50s of elisidepsin were determined using MTT assay in cell lines exposed for the drug concentrations for 72 h. Black bars represent sensitive cell lines 0.4 μM < IC50s < 2.0 μM. KRAS and BRAF mutations, as well as EGFR overexpression, are displayed by specific patterned bars.
Figure 2
Figure 2
Correlation of ErbB3, Muc1 and E-cadherin with elisidepsin sensitivity. Correlation of mRNA expression (qRT-PCR) with elisidepsin IC50s (A) and differential expression in high sensitive and low sensitive groups of cell lines (B).
Figure 3
Figure 3
Role of EMT in elisidepsin activity. Cytotoxicity of 72 h elisidepsin in three isogenic EMT models: Colo205-S/Colo205-R; DLD-1TR21/DLD-Snail; MCF7/MCF7-Wisp.
Figure 4
Figure 4
Resistance to elisidepsin sensitizes cells to tyrosine kinase inhibitors. Cytotoxicity of 72 h elisidepsin in DU145 and its resistant counterpart (DU-PM) (A). Differential relative mRNA expression (qRT-PCR) of several genes in DU145, DU-PM cells and DU145 exposed to 1 μM elisidepsin for 24 h (DU145 + elisidepsin) (B). Protein expression levels of E-cadherin, vimentin, ErbB3 and ErbB1 in DU145 cells exposed to 1 μM elisidepsin for 5 and 24 h, and in DU-PM cells (C). Cytotoxicity of 72 h ErbB1 inhibitors erlotinib, gefitinib and ErbB1/2 inhibitor lapatinib in DU145 and DU-PM cells (D).

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References

    1. Shilabin A.G., Kasanah N., Wedge D.E., Hamann M.T. Lysosome and HER3 (ErbB3) selective anticancer agent kahalalide F: Semisynthetic modifications and antifungal lead-exploration studies. J. Med. Chem. 2007;50:4340–4350. doi: 10.1021/jm061288r. - DOI - PMC - PubMed
    1. Garcia-Rocha M., Bonay P., Avila J. The antitumoral compound kahalalide facts on cell lysosomes. Cancer Lett. 1996;99:43–50. doi: 10.1016/0304-3835(95)04036-6. - DOI - PubMed
    1. Suarez Y., Gonzalez L., Cuadrado A., Berciano M., Lafarga M., Munoz A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol. Cancer. Ther. 2003;2:863–872. - PubMed
    1. Faircloth G.T., Smith B., Grant W., Jimeno J.M., Garcia-Gravalos L., Scotto K., Shtil A. Selective antitumor activity of Kahalalide F, a marine-derived cyclic depsipeptide. Proc. Am. Assoc. Cancer Res. 2001;42:213.
    1. Janmaat M., Rodriguez J., Jimeno J., Kruyt F., Giaccone G. Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol. Pharmacol. 2005;68:502–510. - PubMed

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