Growth inhibition of ovarian tumor-initiating cells by niclosamide
Menée à partir de lignées cellulaires et d'échantillons tumoraux, cette étude identifie, parmi plus de 1 200 molécules autorisées, le niclosamide (un anthelminthique) comme étant doté d'une activité intéressante contre les cellules souches de cancer ovarien
A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that targets such primitive cells. To discover such novel compounds active against drug resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells, from cell lines and patient tumors, using .multiple "stemness" phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTICs) to high throughput drug screening, using > 1200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments demonstrated that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.
http://mct.aacrjournals.org/content/early/2012/05/10/1535-7163.MCT-12-0002.abstract