The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo.
Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC(50) (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.
Lucas
David M
DM
Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. david.lucas@osumc.edu
Edwards
Ryan B
RB
Lozanski
Gerard
G
West
Derek A
DA
Shin
Jungook D
JD
Vargo
Melissa A
MA
Davis
Melanie E
ME
Rozewski
Darlene M
DM
Johnson
Amy J
AJ
Su
Bao-Ning
BN
Goettl
Virginia M
VM
Heerema
Nyla A
NA
Lin
Thomas S
TS
Lehman
Amy
A
Zhang
Xiaoli
X
Jarjoura
David
D
Newman
David J
DJ
Byrd
John C
JC
Kinghorn
A Douglas
AD
Grever
Michael R
MR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000494:pharmacology*; D001572:Benzofurans
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014315:Triterpenes; C579094:Mcl1 protein, mouse; C490393:Tcl1 protein, mouse; C489897:silvestrol; D001572:Benzofurans