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Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

Title: Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines
Author: Schepsky, Alexander   orcid.org/0000-0003-3671-477X
Traustadóttir, Gunnhildur Ásta
Jóelsson, Jón Pétur
Ingþórsson, Sævar
Kricker, Jennifer   orcid.org/0000-0002-0757-1936
Bergthorsson, Jon Thor   orcid.org/0000-0002-0560-2639
Ásbjarnarson, Árni
Gudjonsson, Thorkell   orcid.org/0000-0002-5230-4263
Nupponen, Nina
Slipicevic, Ana
... 2 more authors Show all authors
Date: 2020-07-27
Language: English
Scope: 6726-6738
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Lífvísindasetur (HÍ)
Biomedical Center (UI)
Series: Cancer Medicine;9(18)
ISSN: 2045-7634
DOI: 10.1002/cam4.3300
Subject: Alkylator; Aminopeptidases; Breast cancer; Breast cancer cell lines; Melflufen; Brjóstakrabbamein; Krabbameinsrannsóknir; Lyfjagjöf
URI: https://hdl.handle.net/20.500.11815/2399

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Schepsky, A, Traustadottir, GA, Joelsson, JP, et al. Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines. Cancer Medicine 2020; 9: 6726– 6738. https://doi.org/10.1002/cam4.3300


Melphalan flufenamide (hereinafter referred to as “melflufen”) is a peptide-conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal-derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA-MB231. The tumorigenic D492HER2 and MDA-MB231 cells were more sensitive than normal-derived D492 cells when treated with melflufen. Compared to the commonly used anti-cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA-MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13high and CD13low subpopulations of D492HER2 cells and knockdown of CD13 showed that melflufen efficacy is mediated at least in part by CD13. Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti-neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases.


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