The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cells.
2-methyl-naphtho[2,3-b]furan-4,9-dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin-C and adriamycin, the cytotoxicity of FNQ3 is often 10- to 14-fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose-dependent fashion (50% inhibitory concentration approximately 1.25 microg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL-60 myeloid cells in the presence of either 1alpha, 25(OH)(2) dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] or all-trans-retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.
Desmond
Julian C
JC
Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. jcdesmon@usc.edu
Kawabata
Hiroshi
H
Mueller-Tidow
Carsten
C
Simamura
Eriko
E
Heber
David
D
Hirai
Kei-Ichi
K
Koeffler
H Phillip
HP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C106805:2-methylnaphtho(2,3-b)furan-4,9-dione; D000970:Antineoplastic Agents; D009285:Naphthoquinones