A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.

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Ray A, Ravillah D, Das DS, Song Y, Nordstrom E, Gullbo J, Richardson PG, Chauhan D, Anderson KC

A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.

Br J Haematol. 2016 Aug;174(3):397-409. doi: 10.1111/bjh.14065. Epub 2016 Apr 20.

PubMed ID

27098276 [ View in PubMed

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Abstract

Our prior study utilized both in vitro and in vivo 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 gamma-H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of gamma-H2AX. Melflufen induces gamma-H2AX, ATR, and CHK1 as early as after 2 h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces gamma-H2AX in melphalan-sensitive cells at 6 h and 24 h; no gamma-H2AX induction was observed in melphalan-resistant cells even after 24 h 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 (2 h) 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.

DrugBank Data that Cites this Article

Drugs

Melphalan flufenamide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Melphalan flufenamide	DNA	Nucleotide	Humans	Yes	Cross-linking/alkylation	Details