The effect of cantharidins on leukemic stem cells

• Published in: International journal of cancer Vol. 124; no. 9; pp. 2186 - 2199
• Main Authors: Dorn, David C., Kou, Cynthia A., Png, Kim J., Moore, Malcolm A.S.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-05-2009; Wiley-Blackwell
• Subjects: AML xenograft model; Animals; Antibiotics, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; Arylamine N-Acetyltransferase - antagonists & inhibitors; Basic-Leucine Zipper Transcription Factors - metabolism; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cantharidin - pharmacology; cantharidin norcantharidin; Caspases - metabolism; Cell Cycle - drug effects; Colony-Forming Units Assay; Cytarabine - pharmacology; Daunorubicin - pharmacology; Enzyme Inhibitors - pharmacology; Female; Fetal Blood - cytology; Fetal Blood - drug effects; Fetal Blood - metabolism; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; leukemic stem cells; LSC in vitro model; Luminescence; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phosphorylation - drug effects; Proto-Oncogene Proteins c-myc - metabolism; Snail Family Transcription Factors; STAT5 Transcription Factor - metabolism; Stromal Cells - drug effects; Stromal Cells - metabolism; Survival Rate; Transcription Factors - metabolism; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism; Tumors; cantharidin norcantharidin; Acute myelogenous leukemia; Cancerology; AML xenograft model; leukemic stem cells; Animal; Stem cell; Malignant hemopathy; Models; LSC in vitro model; In vitro; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24157

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.