The effect of cantharidins on leukemic stem cells Journal Article
| Authors: | Dorn, D. C.; Kou, C. A.; Png, K. J.; Moore, M. A. S. |
| Article Title: | The effect of cantharidins on leukemic stem cells |
| Abstract: | To identify an agent with specific activity against leukemic stem cells (LSCs), we evaluated compounds that targeted hepatic leukemia factor (HLF), a gene implicated in hematopoietic stem cell (HSCs) regulation, that we found overexpressed in LSCs. Cantharidin, a natural toxin from blister beetles, used as medicinal agent since antiquity, has been described to modulate the HLF competitor NFIL3 and is under clinical evaluation as an antitumor and antimetastatic agent. The molecule is not a substrate for multidrug resistant pumps and does not cause myelosuppression, and therefore it represents a promising compound for selective ablation of LSCs. Cantharidin and norcantharidin, a derivative with reduced toxicity, decreased HLF protein levels and induced apoptosis in the AML cell line MV4-11 by modulating the expression of several molecules that govern survival pathway, including HLF, SLUG, NFIL3 and c-myc, thereby inducing p53 and the mitochondrial caspase cascade. In vitro, cantharidin readily targeted primary AML stem and progenitor cells in contrast to conventional chemotherapeutic agents, such as Ara-C and daunorubicin, that mainly targeted more differentiated leukemic cells. In vitro the compound did not exhibit a therapeutic window, being equally toxic to normal HSCs and LSCs. In vivo cantharidin did not produce myelosuppression. Because of dose-limiting toxicity in vivo, neither cantharidin nor norcantharidin proved therapeutical benefit in AML xenograft models as a single agent. However, its potent in vitro LSC activity and pathway targeting may still be exploited clinically with a new generation of cantharidin derivatives or formulations and with appropriate drug combinations. © 2008 Wiley-Liss, Inc. |
| Keywords: | cancer survival; controlled study; human tissue; survival rate; unclassified drug; acute granulocytic leukemia; leukemia, myeloid, acute; drug activity; nonhuman; cytarabine; mouse; animal; cytology; metabolism; mouse mutant; animals; mice; animal tissue; gene targeting; cell cycle; apoptosis; gene expression; bone marrow suppression; antimetabolites, antineoplastic; animal experiment; animal model; transcription factor; in vivo study; drug effect; pathology; mice, scid; enzyme inhibitor; caspase; caspases; phosphorylation; protein p53; transcription factors; molecular cloning; drug antagonism; fetal blood; fetus blood; xenograft; luminescence; neoplastic stem cells; enzyme inhibitors; myc protein; tumor protein; cancer stem cell; daunorubicin; transplantation, heterologous; tumor suppressor protein p53; gene control; caspase 8; caspase 9; hematopoietic stem cell; antibiotics, antineoplastic; mice, inbred nod; stroma cell; aml xenograft model; cantharidin norcantharidin; leukemic stem cells; lsc in vitro model; cantharidin; norcantharidin; protein nfil3; transcription factor slug; antineoplastic antibiotic; antineoplastic antimetabolite; arylamine acetyltransferase; basic leucine zipper transcription factor; fused heterocyclic rings; hlf protein, human; myc protein, human; nfil3 protein, human; snail family transcription factors; stat5 protein; tp53 protein, human; cell level; hlf gene; mitochondrial membrane; tumor gene; clonogenic assay; nonobese diabetic mouse; arylamine n-acetyltransferase; basic-leucine zipper transcription factors; bicyclo compounds, heterocyclic; colony-forming units assay; proto-oncogene proteins c-myc; stat5 transcription factor; stromal cells |
| Journal Title: | International Journal of Cancer |
| Volume: | 124 |
| Issue: | 9 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2009-05-01 |
| Start Page: | 2186 |
| End Page: | 2199 |
| Language: | English |
| DOI: | 10.1002/ijc.24157 |
| PUBMED: | 19123473 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: IJCNA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work