The effect of cantharidins on leukemic stem cells.
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.
Dorn
David C
DC
Moore Laboratory, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. dornd@mskcc.org
Kou
Cynthia A
CA
Png
Kim J
KJ
Moore
Malcolm A S
MA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002193:Cantharidin / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049449:Luminescence; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D050976:Basic-Leucine Zipper Transcription Factors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C490671:HLF protein, human; C489427:MYC protein, human; C497440:NFIL3 protein, human; D016271:Proto-Oncogene Proteins c-myc; C000604407:SNAI1 protein, human; D050799:STAT5 Transcription Factor; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; C069741:norcantharidin; D001191:Arylamine N-Acetyltransferase; D020169:Caspases; D002193:Cantharidin; D003630:Daunorubicin