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A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells
Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA..
Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA..
Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA..
Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA..
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2016 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 3, 397-409 p.Article 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, 397-409 p.
Keyword [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: diva2:971317
Funder
NIH (National Institute of Health), P50100707 PO1-CA078378 RO1 CA050947
Available from: 2016-09-16 Created: 2016-09-15 Last updated: 2016-09-16Bibliographically approved

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Gullbo, Joachim
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