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.

Bioactive component, cantharidin from Mylabris cichorii and its antitumor activity against Ehrlich ascites carcinoma

“…Cantharidin has been shown to be active in cervical, tongue, gingival, mucoepidermoid carcinoma, adenocystic carcinoma, neuroblastoma, bone, ovarian, and colon cancer cell lines among others (Wu et al 1992;McCluskey et al 2000;Sakoff et al 2002). Effect of cantharidins against hepatocellular and colorectal tumors (Wang et al 2000;To et al 2005;Chen et al 2005) and leukemic stem cells (Dorn et al 2009) has been well documented.…”

Helminthes and insects: maladies or therapies

“…Cantharidin has anti-cancer activity inhibiting human leukemia cell lines growth in vitro (Rauh et al 2007). Unlike other chemotherapeutic agents, cantharidin acts on leukemia progenitor and stem cells (Dorn et al 2009). Derivatives of cantharidin also inhibit the growth of prostate, colon, oral, cervical, and gall bladder cancer cell lines (Hill et al 2007;Liu and Chen 2009).…”

Cantharidin Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing Autophagy and Inducing Apoptosis in Vitro and in Vivo

“…and Mylabris cichorii Linn. ), is used as a traditional Chinese medicine with anticancer, antibiotic, antiviral, and immune-regulating activities [6,7]. Recent studies have shown that cantharidin and its derivatives exert cytotoxic effects against cancer cells.…”