The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.
Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappaB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
Guzman
Monica L
ML
University of Rochester School of Medicine, 601 Elmwood Ave, Box 703, Rochester, NY 14642, USA. monica_guzman@urmc.rochester.edu
Rossi
Randall M
RM
Karnischky
Lilliana
L
Li
Xiaojie
X
Peterson
Derick R
DR
Howard
Dianna S
DS
Jordan
Craig T
CT
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D007783:Lactones; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C002669:parthenolide