A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cellsShow others and affiliations
2016 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 3, p. 397-409Article in journal (Refereed) Published
Abstract [en]
Our prior study utilized both invitro and invivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via -H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of -H2AX. Melflufen induces -H2AX, ATR, and CHK1 as early as after 2h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces -H2AX in melphalan-sensitive cells at 6h and 24h; no -H2AX induction was observed in melphalan-resistant cells even after 24h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells.
Place, publisher, year, edition, pages
2016. Vol. 174, no 3, p. 397-409
Keywords [en]
Myeloma, apoptosis, novel therapeutics, alkylating agents, melflufen, melphalan
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-303288DOI: 10.1111/bjh.14065ISI: 000380729200006PubMedID: 27098276OAI: oai:DiVA.org:uu-303288DiVA, id: diva2:971317
Funder
NIH (National Institute of Health), P50100707 PO1-CA078378 RO1 CA0509472016-09-162016-09-152022-10-31Bibliographically approved